Nitrogen-containing heterocyclic compounds and therapeutic agents for hyperlipidemia comprising the same

ABSTRACT

Disclosed are compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof. The compounds can inhibit the biosynthesis of triglycerides in the liver and can inhibit the secretion of lipoprotein containing apolipoprotein B from the liver. Therefore, they are useful for the prevention or treatment of hyperlipidemia (particularly hyper-very-low-density-lipoproteinemia) and arteriosclerotic diseases, such as cardiac infarction, or pancreatitis induced by hyperlipidemia.  
                 
 
     wherein A represents group —CR 1 R 2 —( CH 2  ) 1 — where R 1  and R 2  each represent a hydrogen atom or alkyl, —CH═CH—, —O—CH 2 —, or —S(O) j —CH 2 —; B represents a hydrogen or halogen atom; X represents —CR 3 R 4 R 5 , —NR 6 R 7 , —(CH 2 —CH═C(CH 3 )—CH 2 ) p —CH 2 CH═C(CH 3 ) 2 , alkyl, cycloalkyl, phenyl, cinnamyl, or heteroaromatic ring; Y represents —(CH 2 ) q —, —CH═CH—, —NR 8 —, an oxygen atom, or a bond; z represents carbonyl or a bond; K represents alkylene or a bond; L represents —CH═CH— or a bond; and M represents a hydrogen atom, alkyl, cycloalkyl, phenyl, heterocyclic ring, biphenyl, or diphenylmethyl.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to compounds having inhibitoryactivity against the biosynthesis of triglycerides and inhibitoryactivity against the secretion of lipoprotein containing apolipoproteinB, and prophylactic or therapeutic agents for hyperlipidemia comprisingthe same.

[0003] 2. Background Art

[0004] A change in eating habits and an increase in the aged populationhave resulted in increased arteriosclerotic diseases. One of major riskfactors of this group of diseases is an abnormal increase in cholesterolor triglycerides (hyperlipidemia). For example, the proportion offamilial composite hyperlipidemia (FCHL) in patients suffering fromcardiac infarction is about 30% which is higher than other basaldiseases, and hyperlipidemia is known to be a basal disease which has ahigh risk of onset of ischemic heart disease (Lipid, 2, 373 (1991)).

[0005] Further, hyperlipidemia, which is a complication of obesity ordiabetes, has been recognized as a risk factor of arteriosclerosis(Diabetes, 37, 1595(1988) and Int. J. Obesity, 15, 1 (1991).

[0006] Among various types of hyperlipidemia, hypertriglyceridemia isknown to involve a complication of pancreatitis or the like (MedicalPractice, 12, 957 (1995)).

[0007] Therefore, the treatment of hyperlipidemia is important for theprevention or treatment of arteriosclerotic diseases, such as ischemicheart diseases and cerebrovascular diseases, or pancreatitis. Further,it has been pointed out that there is a possibility that hyperlipidemiainvolved in renal diseases progresses renal disorders (MolecularMedicine, 31, 536(1994)). This has led to a proposal on the necessity oftreating hyperlipidemia.

[0008] For the treatment or prevention of hyperlipidemia andarteriosclerotic diseases, medicaments for inhibiting the biosynthesisof cholesterol, particularly statin compounds (such as lovastatin) asmedicaments for inhibiting 3-hydroxy-3-methylglutaryl-coenzyme Areductase and fibrate compounds (such as bezafibrate) as medicaments forreducing the level of triglycerides have been clinically used aspharmaceuticals.

[0009] Further, in recent years, reducing the serum triglyceride valueand the level of serum apolipoprotein B-containing lipoprotein, whichhas been considered to induce arteriosclerosis, is expected to beeffective in preventing or treating the above diseases (Arterioscler.Thromb., 12, 1284 (1992) and Circulation, 85, 37 (1992)). One of basesfor this is that arteriosclerosis is not developed in patients sufferingfrom β-alipoproteinemia, from whom apolipoprotein B-containinglipoprotein is not detected in blood (Clin. Chem., 34, B9-12 (1988).

[0010] Pyrrolecarboxylic acid derivatives, sulfonamide derivatives,biphenyl-2-carboxylic acid derivatives, phenylpiperazine derivatives andthe like are known as compounds having the above activity. Further,isoindolone derivatives having a substituent only in their nitrogen atomat the 2-position are known (EP643057Al and W096/26205).

[0011] On the other hand, compounds having piperazine on the benzene inthe isoindolone and isoquinolone skeletons are known (WO96/26187). Thesecompounds, however, are different from the compounds of the presentinvention in the substituent of nitrogen at the 2-position, and, inaddition, have activity as fibrinogen receptor antagonist. Therefore,they and the present invention are different form each other in idea.

[0012] So far as the present inventors know, compounds having inhibitoryactivity against the secretion of apolipoprotein B-containinglipoprotein among the compounds having piperazine on the benzene ring inthe isoindolone and isoquinoline skeletons are not known.

[0013] Accordingly, the development of medicaments, which have activityto reduce the level of serum triglycerides and, based on a novelmechanism of action, activity to reduce the level of apolipoproteinB-containing lipoprotein in blood and, at the same time, do not causeany side effect of the accumulation of lipid such as found inβ-alipoproteinemia within the liver, have been desired for use of thesemedicaments as prophylactic or therapeutic agents for hyperlipidemia orarteriosclerotic diseases, (The Metabolic Basis of Inherited Disease,Sixth edition, 1139 (1989)).

SUMMARY OF THE INVENTION

[0014] The present inventors have now found that novelnitrogen-containing heterocyclic compounds having piperazine on abenzene ring of isoindolone and isoquinolone skeletons or skeletonssimilar thereto have high activity to reduce the level of lipid inblood, particularly high activity to reduce the level of triglyceridesin blood and high activity to reduce the level of lipoprotein containingapolipoprotein B in blood by virtue of inhibitory activity against thebiosynthesis of triglycerides and inhibitory activity against thesecretion of lipoprotein containing apolipoprotein B in the liver, andthus are useful as therapeutic and prophylactic agents forhyperlipidemia, arteriosclerotic diseases, and pancreatitis.

[0015] Thus, according to the present invention, there is provided acompound represented by formula (I) and pharmaceutically acceptable saltand solvate thereof:

[0016] wherein

[0017] A represents

[0018] group —CR¹R²—(CH₂)— wherein R¹ and R², which may be the same ordifferent, each represent a hydrogen atom or alkyl having 1 to 6 carbonatoms and i is an integer of 0 or 1,

[0019] —CH═CH—,

[0020] —O—CH₂—, or

[0021] —S(O)_(j)—CH₂— wherein j is an integer of 0 to 2;

[0022] B represents a hydrogen or halogen atom;

[0023] X represents

[0024] —CR³R⁴R⁵ wherein R³, R⁴, and R⁵, which may be the same ordifferent, each represent a hydrogen atom or phenyl, provided that anyone of R³, R⁴, and R⁵ represents phenyl and one or more hydrogen atomson phenyl may be substituted by a halogen atom, hydroxy, nitro, phenyl,or alkoxy having 1 to 6 carbon atoms,

[0025] —NR⁶R⁷ wherein R⁶ and R⁷, which may be the same or different,each represent a hydrogen atom, phenyl, or benzyl,

[0026] —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is an integer of0 to 2,

[0027] alkyl having 1 to 18 carbon atoms,

[0028] cycloalkyl having 3 to 8 carbon atoms,

[0029] optionally substituted phenyl,

[0030] optionally substituted cinnamyl, or

[0031] a five- or six-membered heteroaromatic ring containing up to twohetero atoms;

[0032] Y represents —(CH₂)_(q)— wherein q is an integer of 1 to 6,

[0033] —CH═CH—,

[0034] —NR⁸— wherein R⁸ represents a hydrogen atom or alkyl having 1 to6 carbon atoms,

[0035] an oxygen atom, or

[0036] a bond;

[0037] Z represents carbonyl or a bond;

[0038] K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond;

[0039] L represents —CH═CH— or a bond; and

[0040] M represents a hydrogen atom,

[0041] optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms,

[0042] optionally substituted phenyl,

[0043] optionally substituted five- or six-membered, saturated orunsaturated heterocyclic ring containing up to two hetero atoms,

[0044] optionally substituted biphenyl, or

[0045] optionally substituted diphenylmethyl.

[0046] The compounds represented by formula (I) according to the presentinvention inhibit the biosynthesis of triglycerides in the liver andinhibit the secretion of lipoprotein containing apolipoprotein B fromthe liver. Therefore, they can exhibit activity to reduce the level ofserum triglycerides and activity to reduce the level of lipoproteincontaining apolipoprotein B in blood and, at the same time, can preventaccumulation of lipid within hepatic cells.

[0047] Accordingly, the compounds represented by formula (I) andpharmacologically acceptable salts and solvates thereof according to thepresent invention are useful for the prevention or treatment ofhyperlipidemia (particularly hyper-very-low-density-lipoproteinemia) andarteriosclerotic diseases, such as cardiac infarction, or pancreatitisinduced by hyperlipidemia.

DETAILED DESCRIPTION OF THE INVENTION

[0048] Definition

[0049] As used herein, the term “alkyl” or “alkoxy” as a group or a partof a group means a straight chain or branched chain alkyl. The term“halogen” used herein means fluorine, chlorine, bromine, or iodine. Theterm “hetero atom” used herein means a nitrogen, oxygen, or sulfur atom.

[0050] Compounds Represented by Formula (I)

[0051] In formula (I), A represents —CR¹R²—(CH₂)₁— wherein R¹ and R²,which may be the same or different, each represent a hydrogen atom oralkyl having 1 to 6 carbon atoms and i is an integer of 0 or 1; —CH═CH—;—O—CH₂—; or —S(O), —CH₂— wherein j is an integer of 0 to 2. Preferably,A represents —CH₂— or —CH₂CH₂—.

[0052] In formula (I), B represents a hydrogen or halogen atom,preferably a hydrogen, fluorine, or chlorine atom.

[0053] X represents

[0054] —CR³R⁴R⁵ wherein R³, R⁴, and R⁵, which may be the same ordifferent, each represent a hydrogen atom or phenyl, provided that anyone of R³, R⁴, and R⁵ represents phenyl and one or more hydrogen atomson phenyl may be substituted by a halogen atom, hydroxy, nitro, phenyl,or alkoxy having 1 to 6 carbon atoms;

[0055] —NR⁶R⁷ wherein R⁶ and R⁷, which may be the same or different,each represent a hydrogen atom, phenyl or benzyl;

[0056] —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is an integer of0 to 2;

[0057] alkyl having 1 to 18 carbon atoms;

[0058] cycloalkyl having 3 to 8 carbon atoms;

[0059] optionally substituted phenyl;

[0060] optionally substituted cinnamyl; or

[0061] a five- or six-membered aromatic ring having up to two heteroatoms.

[0062] Preferred examples of group —CR³R⁴R⁵ represented by X includethose wherein one or two of R³, R⁴, and R⁵ represent phenyl with theremaining one representing a hydrogen atom and the phenyl may beunsubstituted, or alternatively one hydrogen atom on the phenyl may besubstituted by a fluorine or chlorine atom.

[0063] Preferred examples of group —NR⁶R⁷ represented by X include thosewherein R⁶ and R⁷ each represent phenyl or benzyl.

[0064] Preferred examples of group—(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ represented by X include thosewherein p is 1 or 2.

[0065] The alkyl having 1 to 18 carbon atoms represented by X ispreferably alkyl having 1 to 12 carbon atoms, more preferably alkylhaving 1 to 6 carbon atoms.

[0066] The cycloalkyl having 3 to 8 carbon atoms represented by X ispreferably cycloalkyl having 3 to 7 carbon atoms, and preferred examplesthereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

[0067] One or more hydrogen atoms on phenyl represented by X may besubstituted, and an example of substituents usable herein is a groupselected from the group consisting of hydroxy, halogens (preferablyfluorine, chlorine, and bromine) atoms, nitro, alkoxys having 1 to 6carbon atoms (preferably methoxy and ethoxy), and phenyl. When there area plurality of substituents, they may be the same or different.

[0068] One or more hydrogen atoms on cinnamyl represented by X may besubstituted, and an example of substituents usable herein is a groupselected from the group consisting of hydroxy, halogens (preferablyfluorine, chlorine, and bromine) atoms, nitro, phenyl, and alkoxyshaving 1 to 6 carbon atoms (preferably methoxy and ethoxy). When thereare a plurality of substituents, they may be the same or different.

[0069] An example of preferred five- or six-membered heteroaromaticrings containing up to two hetero atoms represented by X is a ringselected from the group consisting of pyridine, thiophene, pyrrole,furan, pyrazole, imidazole, oxazole, thiazole, pyran, pyridazine,pyrimidine, and pyrazine. More preferred examples thereof includepyridine, thiophene, furan, imidazole, oxazole, and thiazole.

[0070] In formula(I), Y represents —(CH₂)_(q) wherein q is an integer of1 to 6; —CH═CH—; —NR⁸— wherein R⁸ represents a hydrogen atom or alkylhaving 1 to 6 carbon atoms, an oxygen atom, or a bond. Preferably, Yrepresents —(CH₂)_(q)— wherein q is an integer of 1 to 6; —NH—; anoxygen atom, or a bond.

[0071] Z represents carbonyl or a bond.

[0072] In formula (I), K represents an optionally substituted alkylenehaving 1 to 6 carbon atoms or a bond, preferably an optionallysubstituted alkylene having 1 to 3 carbon atoms or a bond.

[0073] One or more hydrogen atoms on the alkylene may be substituted,and an examples of substituents usable herein is a group selected fromthe group consisting of hydroxy, halogens (preferably fluorine,chlorine, and bromine) atoms, alkyl having 1 to 6 carbon atoms, andalkoxys having 1 to 6 carbon atoms (preferably methoxy and ethoxy). Whenthere are a plurality of substituents, they may be the same ordifferent.

[0074] L represents —CH═CH— or a bond.

[0075] M represents a hydrogen atom, alkyl having 1 to 6 carbon atoms,cycloalkyl having 3 to 8 carbon atoms, phenyl, a five- or six-memberedheterocyclic ring containing up to two hetero atoms, biphenyl, ordiphenylmethyl, preferably a hydrogen atom, cycloalkyl having 3 to 8carbon atoms, phenyl, five- or six-membered, saturated or unsaturatedheterocyclic ring containing up to two hetero atoms.

[0076] One or more hydrogen atoms on the alkyl represented by M may besubstituted, and an example of substituents usable herein is a groupselected from the group consisting of hydroxyl, halogens (preferablyfluorine, chlorine, and bromine) atoms, amino, alkoxys having 1 to 6carbon atoms (preferably methoxy and ethoxy), and alkoxycarbonyls having1 to 4 carbon atoms (preferably methoxycarbonyl and ethoxycarbonyl).when there are a plurality of substituents, they may be the same ordifferent.

[0077] One or more hydrogen atoms on the cycloalkyl having 3 to 8 carbonatoms represented by M may be substituted, and an example ofsubstituents usable herein is a group selected from the group consistingof hydroxy, halogens (preferably fluorine, chlorine, and bromine) atoms,amino, alkoxys having 1 to 6 carbon atoms (preferably methoxy andethoxy), alkylcarbonyloxys having 1 to 4 carbon atoms (preferablyacetoxy and ethylcarbonyloxy), and alkoxycarbonyls having 1 to 4 carbonatoms (preferably, methoxycarbonyl and ethoxycarbonyl). When there are aplurality of substituents, they may be the same or different.

[0078] One or more hydrogen atoms on the benzene ring having phenyl,biphenyl, or diphenylmethyl represented by M may be substituted, and anexample of substituents usable herein is a group selected from the groupconsisting of alkyls having 1 to 4 carbon atoms, trifluoromethyl, nitro,hydroxyl, halogens (preferably fluorine, chlorine, and bromine) atoms,amino, alkoxys having 1 to 4 carbon atoms (preferably methoxy andethoxy), alkylcarbonyls having 1 to 4 carbon atoms (preferaby acetyl andethylcarbonyl), and alkoxycarbonyls having 1 to 4 carbon atoms(preferably methoxycarbonyl and ethoxycarbonyl). When there are aplurality of substituents, they may be the same or different.

[0079] An example of five- or six-membered, saturated or unsaturatedheterocyclic rings containing up to two hetero atoms represented by M isa ring selected from the group consisting of pyridine, thiophene,pyrrole, furan, pyrazole, imidazole, oxazole, thiazole, pyran,pyridazine, pyrimidine, pyrazine, and oxane. Preferred examples thereofinclude pyridine, thiophene, furan, imidazole, oxazole, thiazole, andoxane. One or more hydrogen atoms on the heterocyclic ring representedby M may be substituted, and examples of substituents usable hereininclude alkyls having 1 to 4 carbon atoms. When there are a plurality ofsubstituents, they may be the same or different.

[0080] Examples of preferred groups represented by formula X—Y—Z—include (a) dibenzylaminoethyl, (b) isoprenyl, (c) geranyl, (d)farnesyl, (e) t-butyloxycarbonyl, (f) ethoxycarbonyl, (g) pivaloyl, (h)cyclohexyl methyl, (i) pyridylmethyl, (j) nicotinoyl, (k) thienylmethyl,(l) benzyl, (m) benzoyl, (n) benzyloxycarbonyl, (o) phenylpropyl, (p)cinnamyl, (q) biphenyl, (r) biphenylmethyl, (s) diphenyl C₁₋₄ alkyl, (t)diphenylmethylcarbonyl, and (u) benzhydryloxycarbonyl. In this case, oneor more hydrogen atoms on the benzene ring in (l) benzyl, (m) benzoyl,(n) benzyloxycarbonyl, (o) phenylpropyl, (p) cinnamyl, (q) biphenyl, (r)biphenylmethyl, (s) diphenyl C₁₋₄ alkyl, (t) diphenylmethylcarbonyl, and(u) benzhydryloxycarbonyl may be substituted, and examples ofsubstituents usable herein include hydroxy, halogens (preferablyfluorine, chlorine, and bromine) atoms, nitro, and C₁-C₆ alkoxys(preferably methoxy and ethoxy).

[0081] Examples of preferred groups represented by formula —K—L—Minclude:

[0082] cycloalkyls having 3 to 8 carbon atoms wherein one or morehydrogen atoms on the cycloalkyl may be substituted by hydroxy oracyloxy having 1 to 4 carbon atoms;

[0083] phenyl-C₁₋₄ alkylene— wherein one or more hydrogen atoms on thephenyl or alkylene may be substituted by hydroxy, a halogen atom, alkoxyhaving 1 to 6 carbon atoms, nitro, alkyl having 1 to 4 carbon atoms,trifluoromethyl, or alkoxycarbonyl having 1 to 4 carbon atom;

[0084] C₃₋₈ cycloalkyl-C₁₋₆ alkylene wherein one or more hydrogen atomson the cycloalkyl may be substituted by hydroxy or acyloxy having 1 to 4carbon atoms;

[0085] alkyls having 1 to 6 carbon atoms wherein one or more hydrogenatoms in the alkyl may be substituted by alkoxycarbonyl having 1 to 4carbon atoms;

[0086] allyl;

[0087] cinnamyl;

[0088] a five- or six-membered heterocylic ring containing up to twohetero atoms-C₁₋₆ alkylene- wherein one or more hydrogen atoms on theheterocyclic ring may be substituted by alkyl having 1 to 4 carbonatoms;

[0089] diphenylmethyl-C₁₋₆ alkylene-; and

[0090] biphenyl-C₁₋₆ alkylene-.

[0091] Among the compounds represented by formula (I) according to thepresent invention, a group of preferred compounds include compoundswherein

[0092] A represents group —CH₂— or —CH₂CH₂—;

[0093] B represents a hydrogen or halogen atom;

[0094] X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as definedabove in connection with formula (I),

[0095] —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined above in connectionwith formula (I),

[0096] —(CH₂—CH═C(CH₃)_(p)—CH₂ )_(p)—CH₂CH═C(CH₃)₂ wherein p is asdefined above in connection with formula (I),

[0097] alkyl having 1 to 18 carbon atoms,

[0098] cycloalkyl having 3 to 8 carbon atoms,

[0099] optionally substituted phenyl, optionally substituted cinnamyl,or

[0100] a five- or six-membered aromatic ring containing up to two heteroatoms;

[0101] Y represents —(CH₂)₁— wherein q is as defined above in connectionwith formula (I),

[0102] —NH—,

[0103] an oxygen atom, or

[0104] a bond;

[0105] Z represents carbonyl or a bond;

[0106] K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond;

[0107] L represents —CH═CH— or a bond; and

[0108] M represents a hydrogen atom,

[0109] optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl,

[0110] an optionally substituted five- or six-membered,

[0111] saturated or unsaturated heterocyclic ring containing up to twohetero atoms,

[0112] optionally substituted biphenyl, or

[0113] optionally substituted diphenylmethyl.

[0114] According to a preferred embodiment of the present invention, agroup of preferred compounds represented by formula (I) according to thepresent invention include a group of compounds represented by formula(II):

[0115] wherein A, B, X, Z, K, L, and M each are as defined above inconnection with formula (I); and Y represents —(CH₂)₁— with q being aninteger of 1 to 6, —NH—, an oxygen atom, or a bond, provided thatcompounds, wherein —K—L—M represents —H, are excluded.

[0116] Among the group of compounds represented by formula (II), a groupof further preferred compounds include compounds wherein

[0117] A represents group —CH₂— or —CH₂CH₂—;

[0118] as B represents a hydrogen or halogen atom;

[0119] X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as definedabove in connection with formula (I),

[0120] —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined above in connectionwith formula (I),

[0121] —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as definedabove in connection with formula (I),

[0122] alkyl having 1 to 18 carbon atoms,

[0123] cycloalkyl having 3 to 8 carbon atoms,

[0124] optionally substituted phenyl,

[0125] optionally substituted cinnamyl, or

[0126] a five- or six-membered heteroaromatic ring containing up to twohetero atoms;

[0127] Y represents —(CH₂)_(q)— with q being an integer of 1 to 6, —NH—,an oxygen atom, or a bond;

[0128] Z represents carbonyl or a bond;

[0129] K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond;

[0130] L represents —CH═CH— or a bond; and

[0131] M represents a hydrogen atom,

[0132] optionally substituted alkyl having 1 to 6 carbon atoms,

[0133] optionally substituted cycloalkyl having 3 to 8 carbon atoms,

[0134] optionally substituted phenyl,

[0135] an optionally substituted five- or six-membered,

[0136] saturated or unsaturated heterocyclic ring containing up to twohetero atoms,

[0137] optionally substituted biphenyl, or

[0138] optionally substituted diphenylmethyl.

[0139] Further, a group of further preferred compounds represented byformula (II) include compounds wherein

[0140] A represents group —CR³R²—(CH₂)_(i)— wherein R¹ and R², which maybe the same or different, each represent a hydrogen atom or alkyl having1 to 6 carbon atoms and i is an integer of 0 or 1,

[0141] —CH═CH—,

[0142] —O—CH₂—, or

[0143] —S(O)_(j)—CH₂— wherein j is an integer of 0 to 2;

[0144] B represents a hydrogen or halogen atom;

[0145] X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as definedabove in connection with formula (I) or

[0146] —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃), wherein p is as definedabove in connection with formula (I);

[0147] Y represents —(CH₂)_(q)— wherein q is an integer of 1 to 6,

[0148] —NH—,

[0149] an oxygen atom, or

[0150] a bond;

[0151] Z represents carbonyl or a bond;

[0152] K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond;

[0153] L represents —CH═CH— or a bond; and

[0154] M represents a hydrogen atom,

[0155] optionally substituted alkyl having 1 to 6 carbon atoms,

[0156] optionally substituted cycloalkyl having 3 to 8 carbon atoms,

[0157] optionally substituted phenyl,

[0158] an optionally substituted, five- or six-membered,

[0159] saturated or unsaturated heterocyclic ring containing up to twohetero atoms,

[0160] optionally substituted biphenyl, or

[0161] optionally substituted diphenylmethyl.

[0162] Further, a group of further preferred compounds represented byformula (II) include compounds wherein

[0163] A represents group —CR³R²—(CH₂)_(i)— wherein R¹, R², and i eachare as defined above in connection with formula (I),

[0164] —CH═CH—,

[0165] —O—CH₂—, or

[0166] —S(O)_(j)—CH₂— wherein j is as defined above in connection withformula (I);

[0167] B represents a hydrogen or halogen atom;

[0168] X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as definedabove in connection with formula (I),

[0169] —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined above in connectionwith formula (I),

[0170] —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as definedabove in connection with formula (I),

[0171] alkyl having 1 to 18 carbon atoms,

[0172] cycloalkyl having 3 to 8 carbon atoms,

[0173] optionally substituted phenyl,

[0174] optionally substituted cinnamyl, or

[0175] a five- or six-membered heteroaromatic ring containing up to twohetero atoms;

[0176] Y represents —(CH₂)_(q)— wherein q is as defined in claim 1,

[0177] —NH—,

[0178] an oxygen atom, or

[0179] a bond,

[0180] Z represents carbonyl or a bond;

[0181] K represents optionally substituted alkylene having 1 to 3 carbonatoms or a bond;

[0182] L represents —CH═CH— or a bond; and

[0183] M represents a hydrogen atom,

[0184] optionally substituted cycloalkyl having 3 to 8 carbon atoms,

[0185] optionally substituted phenyl, or

[0186] an optionally substituted, five- or six-membered heterocyclicring containing up to two hetero atoms.

[0187] Specific examples of compounds represented by formula (I)according to the invention include

[0188]2-cyclohexyl-6-[4-(trans,trans-farnesyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0189]2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0190]6-[4-(N,N-dibenzylaminoethyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0191]2-(4-acetoxy)cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0192]2-benzyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0193]2-cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0194]2-cyclohexyl-6-[4-(2-diphenylethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0195]2-benzyl-6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0196]3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzoxazin-4-one,

[0197]2-cyclohexyl-6-[4-(geranyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0198]2-cyclohexyl-6-[4-(benzhydryl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0199]2-cyclohexyl-6-{4-[3,3-bis(4-chlorophenyl)-1-propyl]piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one,

[0200]2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-2,3-dihydro-1H-isoindol-1-one,

[0201]2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-2,3-dihydro-1H-isoindol-1-one,

[0202]2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-2,3-dihydro-1H-isoindol-1-one,

[0203]2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0204]2-cyclohexylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0205]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0206]2-(4-bromobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0207] Ethyl{6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1-oxo-1,3-dihydro-1H-isoindol-2-yl}acetate,

[0208]2-(4-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0209]2-cyclopropyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0210]2-cyclohexylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0211]2-cyclopropylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0212]2-(2-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0213]2-(3-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0214]6-[4-(benzhydryloxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0215]2-cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2H-isoquinolin-1-one,

[0216]2-cyclohexyl-6-{4-[3,3-bis(4-methoxyphenyl)-1-propyl]piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one,

[0217]2-benzyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0218]2-(4-bromobenzyl)-6-(4-t-butoxycarbonylpiperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one,

[0219]3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzothiazin-4-one,

[0220]2-cyclopropylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0221]7-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0222]5-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0223]4-chloro-2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0224]2-cyclobutyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0225]2-cyclopentyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0226]2-cycloheptyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0227]2-cyclobutylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]2-2,3-dihydro-1H-isoindol-1-one,

[0228]2-cyclopentylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0229]2-cycloheptylmethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0230]2-cyclopropyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0231]2-cyclobutyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0232]2-cyclopentyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0233]2-cycloheptyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0234]2-cyclobutylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0235]2-cyclopentylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0236]2-cycloheptylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0237]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenyl-2,3-dihydro-1H-isoindol-1-one,

[0238]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxyphenyl)-2,3-dihydro-1H-isoindol-1-one,

[0239]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorophenyl)-2,3-dihydro-1H-isoindol-1-one,

[0240]2-(4-chlorophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0241]2-(4-bromophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0242]2-(4-aminophenyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0243]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxyphenyl)-2,3-dihydro-1H-isoindol-1-one,

[0244]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxyphenyl)-2,3-dihydro-1H-isoindol-1-one,

[0245]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylphenyl)-2,3-dihydro-1H-isoindol-1-one,

[0246]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylphenyl)-2,3-dihydro-1H-isoindol-1-one,

[0247]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxybenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0248]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorobenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0249]2-(4-chlorobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0250]2-(4-aminobenzyl)-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0251]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0252]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylbenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0253]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,

[0254]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0255]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorophenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0256]2-(4-chlorophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0257]2-(4-bromophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0258]2-(4-aminophenyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0259]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0260]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxyphenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0261]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxycarbonylphenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0262]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylphenyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0263]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0264]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-fluorobenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0265]2-(4-bromobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0266]2-(4-aminobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0267]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0268]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0269]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1-2-(4-methoxycarbonylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0270]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-ethoxycarbonylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0271] 2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-3,4-dihydro-2H-isoquinolin-1-one,

[0272]2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one,

[0273] 2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-3,4-dihydro-2H-isoquinolin-1-one,

[0274]2-benzyl-4-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0275]2-benzyl-5-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0276]2-benzyl-7-chloro-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0277]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,

[0278]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-5-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,

[0279]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-7-fluoro-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,

[0280]2-cyclohexyl-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0281]2-benzyl-7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0282]2-cyclopropyl-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0283]2-cyclopropyl-7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0284]6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2-phenyl-2,3-dihydro-1H-isoindol-1-one,

[0285]7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2-phenyl-3,4-dihydro-2H-isoquinolin-1-one,

[0286]6-[4-(benzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0287]6-[4-(4-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0288]2-cyclohexyl-6-[4-(3-pyridylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0289]2-cyclohexyl-6-[4-(octadecyl)piperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one,

[0290]2-cyclohexyl-6-[4-(2-thenyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0291] 2-cyclohexyl-6-[4-(cyclohexylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0292]2-cyclohexyl-6-[4-(4-methoxybenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0293]2-cyclohexyl-6-[4-(isoprenyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0294]2-cyclohexyl-6-[4-(4-fluorobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0295]2-cyclohexyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0296] 2-cyclohexyl-6-[4-(3-phenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0297]6-[4-(cinnamyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0298]6-[4-(3-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0299]6-[4-(4-bromobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0300]6-[4-(2-chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0301]2-cyclohexyl-6-[4-(triphenylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0302]2-cyclohexyl-6-[4-(3,4-dichlorobenzyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0303] 2-cyclohexyl-6-[4-(4-biphenylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0304]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxy)cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0305]6-[4-(benzyloxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0306]2-cyclohexyl-6-[4-(ethoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0307] 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0308]6-[4-(benzoyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0309]2-cyclohexyl-6-[4-(pivaloyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0310]2-cyclohexyl-6-[4-(methoxybenzyloxycarbonyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0311]2-cyclohexyl-6-[4-(3,5-dimethoxy-4-hydroxybenzoyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0312]2-cyclohexyl-6-[4-(pyridine-3-carbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0313] 2-cyclohexyl-6-[4-diphenylacetylpiperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0314]2-cyclohexyl-6-[4-(4-hydroxyphenyl)methylpiperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0315]2-cyclohexyl-5-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0316] 2-cyclohexyl-5-[4-(trans,trans-farnesyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0317]6-[4-(t-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0318]6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one,

[0319]6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0320]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0321]6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-chlorobenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0322]6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-methoxy-benzyl)-2,3-dihydro-1H-isoindol-1-one,

[0323]6-(4-t-butoxycarbonylpiperazin-1-yl)-2-cyclopropyl-methyl-2,3-dihydro-1H-isoindol-1-one,

[0324]6-(4-t-butoxycarbonylpiperazin-1-yl)-2-cyclohexyl-methyl-2,3-dihydro-1H-isoindol-1-one,

[0325] 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one,

[0326] 6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one,

[0327]6-(4-t-butoxycarbonylpiperazin-1-yl)-2-(4-nitro-benzyl)-2,3-dihydro-1H-isoindol-1-one,

[0328]Ethyl[6-(4-t-butoxycarbonylpiperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetate,

[0329]2-cyclohexyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0330] 2-cyclohexyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-2H-isoquinolin-1-one,

[0331]2-methyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0332] 7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one,

[0333]2-cyclohexylmethyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0334]2-cyclopropylmethyl-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0335]2-(4-chlorobenzyl)-7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one,

[0336]7-(4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0337]3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0338]3-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-1,3-benzoxazin-4-one,

[0339]2-cyclohexyl-6-[4-(2-diphenylamino-ethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0340]4-(2-cyclohexyl-1-oxo-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylicacid benzhydrylamide,

[0341]7-[4-(benzhydryloxycarbonyl)piperazin-1-yl]-2-benzyl-3,4-dihydro-2H-isoquinolin-1-one,

[0342]2-benzyl-7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0343]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-isopropyl-2,3-dihydro-1H-isoindol-1-one,

[0344]2-alyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0345] 2-cinnamyl-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0346]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0347]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0348]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0349]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-nitrobenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0350]6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-2,3-dihydro-1H-isoindol-1-one,

[0351]2-benzyl-3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,

[0352]3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one,

[0353]3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-2,3-dihydro-1H-isoindol-1-one,

[0354] 2-allyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0355]2-cinnamyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0356]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-phenyl-1-propyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0357]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-phenetyl-3,4-dihydro-2H-isoquinolin-1-one,

[0358]2-(3,3-diphenyl-1-propyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0359]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0360]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0361]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0362]2-(3,4-dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0363]2-(2,5-dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0364]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2,4,6-trimethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0365]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0366]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0367]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0368]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-fluorobenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0369]2-(3-bromobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0370]2-(3,4-dichlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0371]2-(2,4-dichlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0372]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0373]2-(3,5-dimethoxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0374]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,

[0375]2-(3,5-dihydroxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0376]2-(2-hydroxy-2-phenyl)ethyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0377]2-(2-biphenylmethyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,

[0378]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(tetrahydropyran-2-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,

[0379]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,

[0380]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methylthiazol-5-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,

[0381]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,

[0382]7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-2-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one,and

[0383] 2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one.

[0384] The compounds according to the present invention may exist assalts. Preferred salts include pharmaceutically acceptable nontoxicsalts, for example, lithium, sodium, potassium, magnesium, and calciumsalts, salts with ammonia and suitable nontoxic amines, for example,C₁-C₆ alkylamines (for example, triethylamine) salts, C₁- C₆alkanolamines (for example, diethanolamine or triethanolamine) salts,procaine salts, cyclohexylamine (for example, dicyclohexylamine) salts,benzylamine (for example, N-methylbenzylamine, N-ethylbenylamine,N-benzyl-β-phenetylamine, N,N-dibenzylethylenediamine or dibenzylamine)salts, and heterocyclic amines (for example, morpholine orN-ethylpyridine) salts, hydrohalogenic acid salts, such as hydrofluoridesalts, hydrochloride salts, hydrobromide salts, and hydroiodide salts,inorganic acid salts, such as sulfuric acid salts, nitric acid salts,phosphoric acid salts, perchloric acid salts, and carbonic acid salts,carboxylic acid salts, such as acetic acid salts, trichloroacetic acidsalts, trifluoroacetic acid salts, hydroxyacetic acid salts, lactic acidsalts, citric acid salts, tartaric acid salts, oxalic acid salts,benzoic acid salts, mandelic acid salts, butyric acid salts, maleic acidsalts, propionic acid salts, formic acid salts, and malic acid salts,amino acid salts, such as alginic acid salts, aspartic acid salts, andglutamic acid salts, and other organic acid salts, such asmethanesulfonic acid salts and p-toluenesulfonic acid salts. Preferredare acid addition salts, such as trifluoroacetic acid salts,hydrochloric acid salts, sulfuric acid salts, oxalic acid salts,methanesulfonic acid salts, and citric acid salts, and amino acid salts,such as glutamic acid salts and aspartic acid salts.

[0385] The compounds according to the present invention may exist assolvates. Preferred solvates include hydrates of the compounds andsolvation products between the compounds and ethanol.

[0386] Use of Compounds Represented by Formula (I)/PharmaceuticalComposition

[0387] The compounds represented by formula (I) and pharmacologicallyacceptable salts and solvates thereof according to the present inventionhave triglyceride biosynthesis inhibitory activity and inhibitoryactivity against secretion of apolipoprotein B-containing lipoproteinsin liver. Therefore, the compounds according to the present inventioncan lower the amount of serum triglycerides and serum apolipoproteinB-containing lipoproteins, and thus can be used as prophylactic ortherapeutic agents for hyperlipidemia (particularlyhyper-very-low-density-lipoproteinemia) and/or arterioscleroticdiseases, such as cardiac infarction, or pancreatitis induced byhyperlipidemia. The compounds represented by formula (I) according tothe present invention are especially advantageous in that they inhibitbiosynthesis of lipids within hepatic cells and hence are not consideredto have such side effect as will cause accumulation of hepatolipids.

[0388] The compounds and pharmacologically acceptable salts and solvatesthereof according to the present invention may be administered to humanbeings and animals other than human beings by way of any one of routesincluding oral and parenteral administration, such as intravenousinjection, intramuscular injection, subcutaneous administration,intraperitoneal administration, rectal administration, or percutaneousadministration.

[0389] Accordingly, the compounds and pharmacologically acceptable saltsand solvates thereof according to the present invention may be formedinto appropriate dosage forms depending on its administration routes,and specifically prepared primarily into any one of the preparationforms including injections such as intravenous injection andintramuscular injection, preparations for oral administration such ascapsules, tablets, granules, powders, pills, particulates, and troches,preparations for rectal administration, fatty suppositories, and aqueoussuppositories.

[0390] These preparations can be prepared by conventional methods withordinarily used excipients, fillers, binders, humidifiers,disintegrants, surface active agents, lubricants, dispersants, buffers,preservatives, dissolution aids, antiseptics, flavoring agents,analgesic agents, stabilizers and the like. Such non-toxic additivesusable herein include, for example, lactose, fructose, glucose, starch,gelatin, magnesium carbonate, synthetic magnesium silicate, talc,magnesium stearate, methylcellulose or a salt thereof, gum arabic,polyethylene glycol, syrup, petrolatum, glycerol, ethanol, propyleneglycol, citric acid, sodium chloride, sodium sulfite, and sodiumphosphate.

[0391] The content of the compound according to the present invention inthe pharmaceutical composition may vary according to its dosage forms.In general, however, the content of the compound may be about 1 to 70%by weight, preferably about 5 to 50% by weight, based on the wholecomposition.

[0392] The dosage may be appropriately determined in consideration ofthe dosage route and the age, sex, condition of patients and the like,and the preparation may be administered for the treatment ofhyperlipidemia usually in an amount of about 0.1 to 5000 mg, preferably1 to 600 mg per day per adult in one or several portions.

[0393] Synthesis of Compounds Represented by Formula (I)

[0394] Preferably, the compounds represented by formula (I) according tothe present invention are synthesized by the following synthesisprocesses 1 to 10. In the following synthesis, protective groups orC₁-C₄ acyl groups on substituents may be if necessary introduced andremoved by conventional means.

[0395] It will be apparent to a person having ordinary skill in the artthat, in the following production processes, the order of synthesis maybe determined so as not to cause any side reaction in functional groupsnot involved in the reaction and, in addition, functional groups may beprotected by a suitable protective group in order to prevent theprogress of unfavorable reactions.

[0396] Synthesis Process 1

[0397] Among the compounds represented by formula (I), compounds,wherein A represents group —CH₂— or —CH₂CH₂—, are preferably produced bythe following process.

[0398] The first step is an imidation reaction of an acid anhydride. Acompound represented by formula (VI), wherein t is an integer of 1 or 2and B represents a hydrogen or halogen atom, may be reacted with acompound represented by formula H₂N—K—L—M, wherein K, L, and M each areas defined above in connection with formula (I), in the presence orabsence of a base in a solvent not involved in the reaction (forexample, tetrahydrofuran, benzene, toluene, or xylene) or undersolvent-free conditions for 0.5 to 48 hr, preferably 1 to 24 hr, at 50to 200° C., preferably 100 to 180° C., to obtain a compound representedby formula (VII) wherein t is an integer of 1 or 2 and B, K, L, and Meach are as defined above in connection with formula (I).

[0399] The second step is a reduction reaction for converting the imideto a lactam. The compound represented by formula (VII) may be reduced ina solvent not involved in the reaction (for example, acetic acid,N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, ortoluene) in the presence of a reducing agent (for example, zinc-aceticacid, tin, sodium boron hydride, or zinc boron hydride) for 0.5 to 48hr, preferably 1 to 24 hr, at 50 to 200° C., preferably 80-150° C., toobtain a compound represented by formula (VIII) wherein t, B, X, L, andM each are as defined above.

[0400] The third step is a nitration reaction. Conventional nitratingagents may be used in the nitration. The compound represented by formula(VIII) is reacted with a nitrating agent (preferably, nitric acid orpotassium nitrate) in concentrated sulfuric acid for 0.5 to 48 hr,preferably 0.5 to 24 hr, at −20 to 100° C., preferably −20 to 50° C., toobtain a compound represented by formula (IX) wherein t, B, K, L, and Meach are as defined above.

[0401] In the fourth step, the compound represented by formula (IX) isreduced to convert the nitro group to an amino group. Specifically, thisconversion is carried out by catalytic reduction in the presence ofpalladium-carbon, palladium black, palladium hydroxide, platinum oxide,or Raney nickel, a reduction reaction using tin, zinc, iron or the likeand an acid, such as acetic acid, or reduction with sodium boron hydrideor hydrazine, preferably catalytic reduction in the presence ofpalladium-carbon or palladium black or a reduction reaction with ironand acetic acid, in a solvent not involved in the reaction (for example,methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, or benzene)for 0.5 to 48 hr, preferably for 0.5 to 30 hr, at 0 to 100° C.,preferably 0 to 50° C., to obtain a compound represented by formula (X)wherein t, B, K, L, and M each are as defined above.

[0402] The fifth step is piperazination of the amine. The compoundrepresented by formula (X) is reacted in the presence of 1 to 5equivalents of bischloroethylamine and in the presence or absence of 1to 3 equivalents of an acid, such as hydrochloric acid, in a solvent notinvolved in the reaction (for example, n-butanol, xylene, or toluene)for 0.5 hr to 7 days, preferably 1 hr to 5 days, at 50 to 200° C.,preferably 60 to 180° C., to obtain a compound represented by formula(XI) wherein t, B, K, L, and M each are as defined above.

[0403] The sixth step is a condensation reaction with a compoundrepresented by formula X—Y—Z—G. This reaction may be carried out by anyone of the following methods (i) to (iii).

[0404] Method (i): A compound represented by formula X—Y—Z—G, wherein Grepresents a halogen atom, such as chlorine, bromine, or iodine, C₁-C₄alkylsulfonyl such as methanesulfonyl, or arylsulfonyl, such asp-toluenesulfonyl, X and Y each are as defined above in connection withformula (I), and z represents a bond, is reacted with the compoundrepresented by formula (XI) in the presence or absence of a base in asolvent not involved in the reaction (for example, dichloromethane,tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide) for 10min to 48 hr, preferably 10 min to24 hr, at −20 to 150° C., preferably0-100° C., to obtain a compound represented by formula (I) wherein Arepresents —CH₂— or —CH₂CH₂—, B, K, L, M, X, and Y each are as definedabove in connection with formula (I), and z represents a bond).

[0405] Method (ii): The compound represented by formula X—Y—Z—G, whereinX and Y are as defined above in connection with formula (I), Zrepresents carbonyl or, together with group G, represents a carboxylicacid residue which has been activated by an acid halide, an acidanhydride or an activator, is reacted with the compound represented byformula (XI) in the presence or absence of a base in a solvent notinvolved in the reaction (for example, dichloromethane, tetrahydrofuran,N,N-dimethylformamide, or dioxane) for 1 min to 48 hr, preferably 1 minto 24 hr, at −20 to 100° C., preferably 0 to 50° C., to obtain acompound represented by formula (I) wherein A represents —CH₂— or—CH₂CH₂—, B, K, L, M, X, and Y each are as defined above in connectionwith formula (I), and Z represents carbonyl.

[0406] Method (iii): When the compound represented by formula X—Y—Z—G isX—(CH₂)_((q−1))—CHO wherein q represents an integer of 1 to 6 and X isas defined above in connection with formula (I), this compound and thecompound represented by formula (XI) may be subjected to reductivealkylation with 1 to 5 equivalents of a reducing agent, for example, ametal hydride reagent, such as sodium boron cyanohydride, lithium boroncyanohydride, sodium boron hydride, lithium boron hydride, or sodiumboron triacetoxyhydride) in the presence or absence of 0.1 to 5equivalents of an acid, such as acetic acid or hydrochloric acid, in asolvent not involved in the reaction (for example, dichloroethane,dichloromethane, or tetrahydrofuran) for 0.5 to 48 hr, preferably 1 to24 hr, at −20 to 100° C., preferably 0 to 70° C., to obtain a compoundrepresented by formula (I) wherein A represents —CH₂— or —CH₂CH₂—, B, K,L, M, and X each are defined above in connection with formula (I), Yrepresents —(CH₂)_(q)— wherein q is an integer of 1 to 6, and Zrepresents a bond.

[0407] The compound represented by formula (VIII), wherein A represents—CH₂CH₂—, may also be synthesized by the method described in “YakugakuZasshi, 96, 176-179 (1976).

[0408] Bases usable in the reaction in synthesis process 1 includepyridine, triethylamine, N-methylmorpholine, and dimethylaminopyridine.Preferably, the base is used in an amount of 0.1 to 5 equivalents.

[0409] Preferred activators for carboxylic acids in the condensation ofthe compound represented by formula (XI) with the compound representedby X—Y—Z—G in method (ii) include 1,3-dicyclohexylcarbodiimide and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

[0410] Synthesis Process 2

[0411] As described below, among the compounds represented by formula(I), compounds, wherein B represents a halogen atom, may be produced byhalogenating a corresponding compound wherein B represents a hydrogenatom.

[0412] Specifically, the compound represented by formula (I), wherein A,K, L, M, X, Y, and Z each are as defined above in connection withformula (I) and B represents a hydrogen atom), is halogenated using aradical initiator (for example, N-halosuccinimide, preferablyN-chlorosuccinimide, or N-bromosuccinimide) preferably in the presenceof 0.01 to 3 equivalents of 2,2′-azobisisobutyronitrile in a solvent notinvolved in the reaction (for example, carbon tetrachloride,tetrahydrofuran, or benzene) for 0.5 to 48 hr, preferably for 1 to 24hr, at −20 to 150° C., preferably at 0 to 120° C. to give the compoundrepresented by formula (I) wherein B represents a halogen atom.

[0413] Synthesis Process 3

[0414] Among the compounds represented by formula (I), compounds,wherein A represents —CH═CH—, may be produced by dehydrogenatingcorresponding compounds wherein A represents —CH₂CH₂—.

[0415] Specifically, according to the method described in J. Med. Chem.39, 4583-4591 (1996), the compound represented by formula (I), whereinB, K, L, M, X, Y, and Z each are as defined above in connection withformula (I) and A represents —CH₂CH₂—, may be dehydrogenated in thepresence of palladium-carbon or palladium black in a solvent notinvolved in the reaction (for example, methanol, ethanol,tetrahydrofuran, N,N-dimethylformamide, or benzene) for 0.5 to 48 hr,preferably for 0.5 to 30 hr. at 0 to 100° C., preferably at 0 to 80° C.to give the compound represented by formula (I) wherein A represents—CH═CH—.

[0416] Synthesis Process 4

[0417] Among the compounds represented by formula (I), compounds,wherein A represents group —CH₂— or —CH₂CH₂—, may also be producedpreferably through route A or route B.

[0418] Route A:

[0419] According to step 6 in synthesis process 1, a compoundrepresented by formula (XII), wherein t is an integer of 1 or 2 and B isas defined above in connection with formula (I), is condensed with acompound represented by formula X—Y—Z—G wherein X, Y, and Z each are asdefined above in connection with formula (I), G represents a halogenatom, such as chlorine, bromine, or iodine, C₁-C₄ alkylsulfonyl, such asmethanesulfonyl, or arylsulfonyl, such as p-toluenesulfonyl, therebyproviding a compound represented by formula (XIII) wherein t is aninteger of 1 or 2, B, X, Y, and Z each are as defined as above inconnection with formula (I).

[0420] Next, according to the description of J. Med. Chem. 39, 4583-4591(1996) or Synthesis, 79, 527-529 (1979), the compound represented byformula (XIII) is reacted with a compound represented by formula G—K—L—Mwherein G represents a halogen atom, such as chlorine, bromine, oriodine, C₁-C₄ alkylsulfonyl, such as methanesulfonyl, arylsulfonyl, suchas p-toluenesulfonyl, and K, L, and M each are as defined above inconnection with formula (I), thereby providing the compound representedby formula (I) wherein A represents group —CH₂— or —CH₂CH₂—.

[0421] Route B:

[0422] The compound represented by formula (XII) in its piperazine isprotected by a protective group, followed by a reaction according to themethod described in J. Med. Chem. 39, 4583-4591 (1996). Protectivegroups usable for piperazine include conventional protective groupscommonly used in synthesis of peptides, and preferred examples thereofinclude t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, trifluoroacetyl, allyloxycarbonyl andtrityl. At the outset, the compound represented by formula (XII) in itspiperazine portion is protected by a conventional method to give acompound represented by formula (XIV) wherein t is an integer of 1 or 2,B is as defined above in connection with formula (I) and P represents aprotective group of amino. Next, the compound represented by formula(XIV) is reacted with a compound represented by formula G—K—L—M, whereinG, K, L, and M each are as defined above in connection with route A,according the method described in the literature noted above, therebyproviding a compound represented by formula (XV). The protective groupin the compound represented by formula (XV) is removed by a conventionalmethod to give a compound represented by formula (XI). The compoundrepresented by formula (XI) is condensed with a compound represented byformula X—Y—Z—G, wherein X, Y, Z, and G each are as defined above inconnection with route A, according to step 6 in synthesis process 1,thereby providing the compound represented by formula (I) wherein Arepresents group —CH₂— or —CH₂CH₂—.

[0423] Synthesis Process 5

[0424] Among the compounds represented by formula (I), compounds,wherein A represents group —CH₂— or —CH₂CH₂—, may also be producedpreferably by the following process.

[0425] A compound represented by formula (XVI), wherein t is an integerof 1 or 2 and B is as defined above in connection with formula (I), isreacted with a compound represented by formula H₂N—K—L—M according tostep 1 in synthesis process 1, thereby providing a compound representedby formula (XVII). The compound represented by formula (XVII) is thensubjected to a reduction reaction using zinc and acetic acid accordingto step 2 in synthesis process 1 to give a compound represented byformula (XVIII). The acetamide thus obtained is hydrolyzed under acidicconditions to give a compound represented by formula (X). Thereafter,the compound represented by formula (I), wherein A represents group—CH₂— or —CH₂CH₂—, may be produced according to step 5 and later stepsin synthesis process 1.

[0426] Synthesis Process 6

[0427] Among compounds represented by formula (I), compounds wherein Arepresents group —CR¹R²—, where R¹ and R² each represent C₁-C₆ alkyl,may be synthesized by producing a compound represented by formula (XIX)according to the method described in Angew. Chem. Int. Ed. Engl. 7, 373(1968) and then subjecting the compound represented by formula (XIX) tostep 3 and later steps in synthesis process 1 or the method in synthesisprocess 4:

[0428] wherein R¹ and R² each represent C₁-C₆ alkyl and B, K, L, and Meach are as defined above in connection with formula (I).

[0429] Synthesis Process 7

[0430] Among the compounds represented by formula (I), compounds,wherein A represents group —OCH₂—, are preferably produced by thefollowing process.

[0431] A compound represented by formula (XX), wherein J represents ahydrogen atom or nitro and B is as defined above in connection withformula (I), is amidated by the method described in Nobuo Izumiya etal., “Peptide Gosei no Kiso to Jikken (Bases and Experiments onSynthesis of Peptides)” (published by Maruzen Co., Ltd.) to obtain acompound represented by formula (XXI) wherein J is as defined above andB, K, L, and M each are as defined above in connection with formula (I).Next, this compound represented by formula (XXI) is converted to acompound represented by formula (XXII), wherein J is as defined aboveand B, K, L, and M each are as defined above in connection with formula(I), according to the method described in Tetrahedron, 48, 4963 (1992).The compound represented by formula (XXII), wherein J represents ahydrogen atom, is nitrated according to step 3 in synthesis process 1.The compound represented by formula (XXII), wherein J represents nitro,is treated according to step 4 and later steps in synthesis process 1 toobtain the compound represented by formula (I) wherein A representsgroup —OCH₂—.

[0432] Synthesis Process 8

[0433] Among the compounds represented by formula (I), compounds,wherein A represents group —SCH₂—, are preferably produced by thefollowing process.

[0434] A compound represented by formula (XXIII), wherein Q represents ahalogen atom and B is as defined above in connection with formula (I),is amidated by the method described in Nobuo Izumiya et al., “PeptideGosei no Kiso to Jikken (Bases and Experiments on Synthesis ofPeptides)” (published by Maruzen Co., Ltd.) to obtain a compoundrepresented by formula (XXIV) wherein Q is as defined above and B, K, L,and M each are as defined above in connection with formula (I). Next,the compound represented by formula (XXIV) is reacted with 1 to 5equivalents of potassium hydrosulfide or potassium thioacetate in asolvent not involved in the reaction (for example, ethanol,tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, or acetonitrile),and, when potassium thioacetate is used, the reaction product is furtherhydrolyzed. Thus, a compound is obtained which is represented by formula(XXV) wherein B, K, L, and M each are as defined above in connectionwith formula (I). This reaction may be carried out at 0 to 200° C. for 1to 72 hr, preferably at 50 to 150° C. for 1 to 48 hr. The compoundrepresented by formula (XXV) is further treated in step 2 and latersteps in synthesis process 7 to give the compound represented by formula(I) wherein A represents group —SCH₂—.

[0435] Synthesis Process 9

[0436] Among the compounds represented by formula (I), compounds,wherein K and L each represent a bond and M represents optionallysubstituted phenyl or an optionally substituted, saturated orunsaturated, five-membered or six-membered heterocyclic ring containingup to two hetero atoms, are preferably produced by the followingprocess.

[0437] A compound represented by formula (XXVI), wherein t represents aninteger of 1 or 2 and B is as defined above in connection with formula(I), and a compound represented by formula W—OH, wherein W representsC₁-C₃ alkyl, are esterified according to the method described in “JikkenKagaku Koza 22,” 4th edition, edited by The Chemical Society of Japan(published by Maruzen Co., Ltd.), pp. 43-47 to give a compoundrepresented by formula (XXVII). Next, the compound represented byformula (XXVII) is halogenated according to the method described in“Jikken Kagaku Koza 19,” 4th edition, edited by The Chemical Society ofJapan(published by Maruzen Co., Ltd.), pp. 422-438 to give a compoundrepresented by formula (XXVIII) wherein Q represents a halogen atom andt, B, and W each are as defined above. The compound represented byformula (XXVIII) is reacted with a compound represented by formulaH₂N—K—L—M in the presence or absence of a base in a solvent not involvedin the reaction (for example, methanol, ethanol, tetrahydrofuran,N,N-dimethylformamide, or dichloromethane) for 10 min to 48 hr,preferably 10 min to 24 hr, at −20 to 150° C., preferably at 0 to 100°C., to give a compound represented by formula (XXIX) wherein t, B, W, K,L, and M each are as defined above. The compound represented by formula(XXIX) is then reduced in the presence of palladium-carbon according tostep 4 in synthesis process 1 to give a compound represented by formula(XXX) wherein t, B. W, K, L, and M each are as defined above. Thecompound represented by formula (XXX) is reacted in the presence orabsence of a base or an acid in a solvent not involved in the reaction(for example, ethanol, tetrahydrofuran, N,N-dimethylformamide,dichloromethane, or toluene) for 10 min to 48 hr, preferably 10 min to24 hr, at −20 to 150° C., preferably at 0 to 100° C., to give a compoundrepresented by formula (X) wherein t, B, K, L, and X each are as definedabove. The compound represented by formula (X) may be then treated bystep 5 and later steps in synthesis process 1 to give the compoundrepressed by formula (I) wherein K and L represent a bond and Mrepresents an optionally substituted phenyl or an optionallysubstituted, saturated or unsaturated, five- membered or six-memberedheterocyclic ring containing up to two hetero atoms.

[0438] Synthesis Process 10

[0439] Among the compounds represented by formula (I), compounds,wherein A represents group —CR¹R²—CH₂— wherein R¹ and R² each representC_(l)-C₆ alkyl, are preferably produced by synthesizing a compoundrepresented by formula (XXXI) according to the method described in J.Heterocycl. Chem. 7, 615 (1970) and then treating the compoundrepresented by formula (XXXI) according to step 3 and later steps insynthesis process 1 or alternatively the synthesis process 4:

[0440] wherein R¹ and R² each represent C₁-C₆ alkyl; and B is as definedabove in connection with formula (I).

EXAMPLES

[0441] The following examples further illustrate the present invention,but are not intended to limit it.

Example 16-[4-(Benzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0442] (a) Cyclohexylamine (50.20 ml, 0.44 mol) and triethylamine (51.76ml, 0.37 mol) were added to a suspension of phthalic anhydride (50.00 g,0.34 mol) in toluene (500 ml) at room temperature. The mixture wasstirred at 110° C. overnight. The temperature of the system was thenreturned to room temperature, and a 0.1 N aqueous citric acid solutionwas added thereto. The mixture was extracted with ethyl acetate. Theextract was washed with saturated saline and dried over anhydrous MgSO₄.The solvent was then removed by distillation under the reduced pressure.The precipitated crystals were collected by suction filtration, washedwith hexane, and then dried to give 55.28 g (71%) of2-cyclohexylphthalimide as a white crystalline product.

[0443]¹H-NMR(CDCl₃) δ: 1.24-1.45 (3H, m), 1.67-1.75 (3H, m), 1.85-1.89(2H, m), 2.14-2.28 (2H, m), 4.06-4.17 (1H, m), 7.68-7.71 (2H, m),7.80-7.83 (2H, m)

[0444] EIMS(M/Z): 229(M⁺)

[0445] (b) Zinc powder (63.19 g, 0.97 mol) was added at room temperatureto a solution of the compound (22.93 g, 0.1 mol), obtained in step (a)just above, in acetic acid (500 ml). The mixture was stirred at 100° C.for 2 hr. The temperature of the system was returned to roomtemperature, followed by filtration through Celite. The solvent wasremoved from the filtrate by distillation under the reduced pressure.Ethyl acetate was added to the residue. The mixture was washed withwater, a saturated aqueous NaHCO₃ solution, and saturated saline in thatorder, and then dried over anhydrous MgSO₄. The solvent was then removedby distillation under the reduced pressure. The precipitated crystalswere collected by suction filtration, washed with hexane, and then driedto give 15.27 g (71%) of 2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one as awhite crystalline product.

[0446]¹H-NMR(CDCl₃) δ: 1.11-1.24 (1H, m), 1.40-1.55 (4H, m), 1.68-1.80(1H, m), 1.80-1.94 (4H, m), 4.21-4.31 (1H, m), 4.35 (2H, s), 7.42-7.55(3H, m), 7.84-7.87 (1H, m)

[0447] EIMS(M/Z): 215 (M⁺)

[0448] (c) The compound (50.00g, 0.23 mol) obtained in step(b) justabove was dissolved at 0° C. in concentrated sulfuric acid (413 ml).Potassium nitrate (36.63 g, 0.36 mol) was added to the solution. Themixture was stirred overnight while gradually raising the temperaturefrom 0° C. to room temperature. The reaction solution was poured intoice water (2000 ml), and then extracted with ethyl acetate. The extractwas then washed with water, a saturated aqueous NaHCO₃ solution, andsaturated saline in that order, and then dried over anhydrous MgSO₄. Thesolvent was removed by distillation under the reduced pressure. Theprecipitated crystals were collected by suction filtration, washed withhexane, and then dried to give 49.78 g (82%) of2-cyclohexyl-2,3-dihydro-6-nitro-1H-isoindol-1-one as a pale yellowcrystalline product.

[0449]¹H-NMR(CDCl₃) δ: 1.15-1.25 (1H, m), 1.41-1.57 (4H, m), 1.73-1.79(1H, m), 1.83-1.92 (4H, m), 4.24-4.31 (1H, m), 4.48 (2H, s), 7.63 (1H,d, J=8.3 Hz), 8.41 (1H, dd, J=2.1, 8.3 Hz), 8.69 (1H, d, J=2.1 Hz)

[0450] EIMS(M/Z): 260(M⁺)

[0451] (d) 5% palladium-carbon (1 g) was added at room temperature to asolution of the compound (26.03 g, 0.1 mol), obtained in step (c) justabove, in methanol (250 ml), followed by catalytic reduction. Afterstirring at room temperature for 26 hr, the reaction solution wasfiltered through Celite. The solvent was removed from the filtrate bydistillation under the reduced pressure. The precipitated crystals werecollected by suction filtration, washed with hexane, and then dried togive 15.36 g (67%) of 6-amino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one as a brown crystalline product.

[0452]¹H-NMR(CDCl₃) δ: 1.12-1.18 (1H, m), 1.42-1.53 (4H, m), 1.69-1.79(1H, m), 1.83-1.86 (4H, m), 3.82 (2H, br s), 4.22 (1H, m), 4.24 (2H, s),6.83 (1H, dd, J=2.3, 8.0 Hz), 7.12 (1H, d, J=2.3 Hz), 7.20 (1H, d, J=8.0Hz)

[0453] EIMS(M/Z): 230(M⁺)

[0454] (e) Bis(2-chloroethyl)amine hydrochloride (9.82 g, 55.0 mmol) wasadded at room temperature to a solution of the compound (11.52 g, 50.0mmol), obtained in step(d) just above, in xylene (200 ml). The mixturewas then stirred by means of a mechanical stirrer at 140° C. for 3 days.The temperature of the reaction solution was returned to roomtemperature, and a 1 N aqueous sodium hydroxide solution (200 ml) wasadded thereto. The mixture was extracted with ethyl acetate. The extractwas washed with saturated saline, and then dried over anhydrous MgSO₄.The solvent was then removed by distillation under the reduced pressure.The precipitated crystals were collected by suction filtration, washedwith hexane and diethyl ether in that order, and then dried to give11.33 g (76%) of2-cyclohexyl-2,3-dihydro-6-(piperazin-1-yl)-1H-isoindol-1-one as a paleyellow crystalline product.

[0455]¹H-NMR(CDCl₃) δ: 1.13-1.26 (1H, m), 1.43-1.54 (4H, m), 1.69-1.76(1H, m), 1.80-1.90 (4H, m), 3.04-3.08 (4H, m), 3.19-3.22 (4H, m), 4.25(1H, m), 4.27 (2H, s), 7.11 (1H, dd, J=2.4, 8.4 Hz), 7.31 (1H, d, J=8.4Hz), 7.36 (1H, d, J=2.4 Hz)

[0456] EIMS(M/Z): 299(M⁺)

[0457] (f) Potassium carbonate (111 mg, 0.8 mmol) and benzyl bromide(0.048 ml, 0.4 mmol) were added at 0° C. to a solution of the compound(120 mg, 0.4 mmol), obtained in step (e) just above, in dichloromethane(2 ml). The mixture was stirred for one day while gradually raising thetemperature from 0° C. to room temperature. A 0.1 Naqueous citric acidsolution was then added thereto. The mixture was then extracted withethyl acetate. The extract was washed with saturated saline, and thendried over anhydrous MgSO₄. The solvent was then removed by distillationunder the reduced pressure. The residue was then purified by columnchromatography on silica gel (hexane : ethyl acetate=1:1) to give 99 mg(64%) of the title compound.

[0458]¹H-NMR(CDCl₃) δ: 1.12-1.22 (1H, m), 1.38-1.53 (4H, m), 1.68-1.78(1H, m), 1.78-1.86 (4H, m), 2.61-2.64 (4H, m), 3.23-3.26 (4H, m), 3.57(2H, s), 4.23 (1H, m), 4.26 (2H, s), 7.09 (1H, dd, J=2.4, 8.3 Hz),7.24-7.37 (7H, m)

[0459] ESIMS (M/Z): 390(M+H)⁺

Example 26-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0460] The title compound was obtained in the same manner as in step (f)of Example 1, except that 4-chloro benzyl bromide was used instead ofbenzyl bromide.

[0461]¹H-NMR(CDCl₃) δ: 1.12-1.25 (1H, m), 1.38-1.53 (4H, m), 1.64-1.79(1H, m), 1.80-1.86 (4H, m), 2.59-2.62 (4H, m), 3.22-3.26 (4H, m), 3.53(2H, s), 4.24 (1H, m), 4.26 (2H, s), 7.09 (1H, dd, J=2.3, 8.4 Hz),7.29-7.33 (5H, m), 7.35 (1H, d, J=2.3 Hz)

[0462] TSIMS (M/Z): 424(M+H)⁺

Example 32-Cyclohexyl-2,3-dihydro-6-[4-(3-pyridylmethyl)-piperazin-1-yl]-1H-isoindol-1-one

[0463] The title compound was obtained in the same manner as in step (f)of Example 1, except that 3-pyridylmethyl chloride hydrochloride wasused instead of benzyl bromide.

[0464]¹H-NMR(CDCl₃) δ:1.13-1.26 (1H, m), 1.43-1.53 (4H, m), 1.69-1.80(1H, m),1.81-1.92 (4H, m), 2.62-2.65 (4H, m),3.23-3.27 (4H, m), 3.59(2H, s), 4.23 (1H, m), 4.26 (2H, s), 7.10 (1H, dd, J=2.3, 8.4 Hz), 7.29(1H, d, J=7.8 Hz), 7.31 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=2.3 Hz), 7.72(1H, d, J=7.8 Hz), 8.52-8.58 (2H, m)

[0465] TSIMS(M/Z): 391(M+H)⁺

Example 42-Cyclohexyl-2,3-dihydro-6-[4-(octadecyl)piperazin-1-yl]-1H-isoindol-1-one

[0466] The title compound was obtained in the same manner as in step (f)of Example 1, except that octadecyl bromide was used instead of benzylbromide.

[0467]¹H-NMR(CDCl₃) δ: 0.88 (1H, t, J=6.7 Hz), 1.18-1.22 (1H, m),1.25-1.31 (30H, m), 1.43-1.53 (6H, m), 1.70 (1H, m), 1.75-1.87 (4H, m),2.36-2.41 (2H, m), 2.60-2.63 (4H, m), 3.24-3.28 (4H, m), 4.24 (1H, m),4.26 (2H, s), 7.11 (1H, dd, J=2.3, 8.4 Hz), 7.31 (1H, d, J=8.4 Hz), 7.36(1H, d, J=2.3 Hz)

[0468] TSIMS(M/Z): 552(M+H)⁺

Example 52-Cyclohexyl-2,3-dihydro-6-[4-(trans,trans-farnesyl)piperazin-1-yl]-1H-isoindol-1-one

[0469] The title compound was obtained in the same manner as in step (f)of Example 1, except that trans, trans-farnesyl bromide was used insteadof benzyl bromide.

[0470]¹H-NMR(CDCl₃) δ: 1.15-1.19 (1H, m), 1.43-1.53 (4H, m), 1.61 (6H,s), 1.67 (3H, s), 1.68 (3H, s), 1.73-1.80 (1H, m), 1.81-1.94 (4H, m),1.95-2.03 (2H, m), 2.05-2.18 (6H, m), 2.61-2.65 (4H, m), 3.05 (2H, d,J=6.9 Hz), 3.25-3.28 (4H, m), 4.25 (1H, m), 4.26 (2H, s), 5.07-5.12 (2H,m), 5.28-5.33 (1H, m), 7.11 (1H, dd, J=2.4, 8.3 Hz), 7.31 (1H, d, J=8.3Hz), 7.36 (1H, d, J=2.4 Hz)

[0471] TSIMS(M/Z): 504(M+H)⁺

Example 62-Cyclohexyl-2,3-dihydro-6-[4-(2-thenyl)piperazin-1-yl]-1H-isoindol-1-one

[0472] The title compound was obtained in the same manner as in step(f)of Example 1, except that 2-thenyl chloride was used instead of benzylbromide.

[0473]¹H-NMR(CDCl₃) δ: 1.13-1.20 (1H, m), 1.43-1.53 (4H, m), 1.70-1.79(1H, m),1.80-1.92 (4H, m),2.65-2.68 (4H, m),3.25-3.28 (4H, m), 3.79 (2H,s), 4.24 (1H, m), 4.26 (2H, s), 6.95-6.98 (2H, m), 7.09 (1H, dd, J=2.3,8.3 Hz), 7.25 (1H, m), 7.30 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.3 Hz)

[0474] TSIMS(M/Z): 396(M+H)⁺

Example 72-Cyclohexyl-6-[4-(cyclohexylmethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0475] The title compound was obtained in the same manner as in step (f)of Example 1, except that cyclohexylmethyl bromide was used instead ofbenzyl bromide.

[0476]¹H-NMR(CDCl₃) δ: 0.83-0.97 (2H, m), 1.10-1.33 (5H, m), 1.38-1.58(5H, m), 1.63-1.92 (9H, m), 2.04-2.21 (2H, m), 2.54-2.58 (4H, m),3.22-3.26 (4H, m), 4.23 (1H, m), 4.26 (2H, s), 7.10 (1H, dd, J=2.4, 8.5Hz), 7.30 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=2.4 Hz)

[0477] TSIMS(M/Z): 396(M+H)⁺

Example 82-Cyclohexyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0478] The title compound was obtained in the same manner as in step (f)of Example 1, except that 3,3-diphenyl-1-propyl bromide was used insteadof benzyl bromide.

[0479]¹H-NMR(CDCl₃) δ: 1.19-1.23 (1H, m), 1.43-1.49 (4H, m), 1.69-1.74(1H, m), 1.83-1.86 (4H, m), 2.27-2.36 (4H, m),2.56-2.60 (4H, m),3.22-3.26 (4H, m), 4.02 (1H, t, J=7.2 Hz), 4.25 (1H, m), 4.26 (2H, s),7.19 (1H, dd, J=2.3, 8.3 Hz), 7.16-7.20 (2H, nm), 7.25-7.28 (8H, m),7.30 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.3 Hz)

[0480] TSIMS(M/Z): 494 (M+H)⁺

Example 92-Cyclohexyl-2,3-dihydro-6-[4-(4-methoxybenzyl)-piperazin-1-yl]-1H-isoindol-1-one

[0481] The title compound was obtained in the same manner as in step (f)of Example 1, except that 4-methoxybenzyl chloride was used instead ofbenzyl bromide.

[0482]¹H-NMR(CDCl₃) δ: 1.18-1.25 (1H, m), 1.43-1.53 (4H, m)), 1.69-1.77(1H, m), 1.81-1.86 (4H, m), 2.59-2.62 (4H, m), 3.22-3.26 (4H, m), 3.51(2H, s), 3.81 (3H, s), 4.23 (1H, m), 4.26 (2H, s), 6.86-6.90 (2H, m),7.09 (1H, dd, J=2.3, 8.4 Hz), 7.24-7.31 (3H, m), 7.34 (1H, d, J=2.3 Hz)

[0483] TSIMS(M/Z): 420(M+H)⁺

Example 102-Cyclohexyl-2,3-dihydro-6-[4-(isoprenyl)piperazin-1-yl]-1H-isoindol-1-one

[0484] Title compound was obtained in the same manner as in step (f) ofExample 1, except that isoprenyl bromide was used instead of benzylbromide.

[0485]¹H-NMR (CDCl₃) δ:7.38-7.25 (2H, m), 7.11 (1H, m), 5.32 (1H, brs),4.23 (2H, s), 4.22 (1H, brs), 3.28 (4H, t, J=4.5 Hz), 3.16 (2H, d, J=7.0Hz), 2.66 (4H, t, J=4.5 Hz), 1.93-0.97 (16H, m)

[0486] ESIMS(m/z): 368(M+H)⁺

Example 112-Cyclohexyl-2,3-dihydro-6-[4-(geranyl)piperazin-1-yl]-1H-isoindol-1-one

[0487] The title compound was obtained in the same manner as in step (f)of Example 1, except that geranyl bromide was used instead of benzylbromide.

[0488]¹H-NMR(CDCl₃) δ: 7.36 (1H, d, J=2.4 Hz), 7.31 (1H, d, J=7.1 Hz),7.15 (1H, dd, J=2.2, 8.0 Hz), 5.30 (1H, m), 5.10 (1H, m), 4.27 (2H, s),4.25 (1H, brs), 3.26 (4H, t, J=4.5 Hz), 3.04 (2H, d, J=7.1 Hz), 2.63(4H, t, J=5.2 Hz), 2.11 (2H, m), 1.76 (2H, m)

[0489] ESIMS(m/z): 436(M+H)⁺

Example 122-Cyclohexyl-2,3-dihydro-6-[4-(4-fluorobenzyl)-piperazin-1-yl]-1H-isoindol-1-one

[0490] The title compound was obtained in the same manner as in step(f)of Example 1, except that 4-fluoro benzyl bromide was used instead ofbenzyl bromide.

[0491]¹H-NMR(CDCl₃) δ:7.36-7.28 (4H, m), 7.12-6.98 (3H, m), 4.27 (2H,s), 4.23 (1H, brs), 3.53 (4H, t, J=4.7 Hz), 2.60 (4H, t, J=4.7 Hz),1.83-1.18 (10H, m)

[0492] EIMS(m/z): 407(M⁺)

Example 132-Cyclohexyl-2,3-dihydro-6-[4-(4-nitrobenzyl)-piperazin-1-yl]-1H-isoindol-1-one

[0493] The title compound was obtained in the same manner as in step (f)of Example 1, except that 4-nitro benzyl bromide was used instead ofbenzyl bromide.

[0494]¹H-NMR (CDCl₃) δ:8.21 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz),7.36 (2H, m), 7.13 (1H, dd, J=2.3, 7.6 Hz), 4.27 (2H, s), 4.23 (1H,brs), 3.53 (4H, t, J=4.7 Hz), 2.60 (4H, t, J=4.7 Hz), 1.83-1.18 (10H, m)

[0495] FABMS(m/z): 435(M+H)⁺

Example 142-Cyclohexyl-2,3-dihydro-6-[4-(benzhydryl)-piperazin-1-yl]-1H-isoindol-1-one

[0496] The title compound was obtained in the same manner as in step (f)of Example 1, except that benzhydryl bromide was used instead of benzylbromide.

[0497]¹H-NMR(CDCl₃) δ:7.45 (4H, d, J=8.0 Hz), 7.34-7.25 (6H, m), 7.19(2H, t, J=8.0 Hz), 7.07 (1H, dd, J=2.2, 8.3 Hz), 4.26 (4H, m), 3.23 (4H,t, J=4.7 Hz), 2.58 (4H, t, J=4.7 Hz), 1.83-1.18 (10H, m)

[0498] EIMS(m/z): 465(M⁺)

Example 15 6-[4-(N,N-Dibenzylamino-2-ethyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0499] The title compound was obtained in the same manner as in step (f)of Example 1, except that N,N-dibenzylaminoethyl chloride hydrochloridewas used instead of benzyl bromide.

[0500]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.39-1.54 (4H, m), 1.69-1.80 (1H,m), 1.84-1.89 (4H, m), 2.53-2.56 (4H, m), 2.59-2.67 (4H, m), 3.18-3.21(4H, m), 3.62 (4H, s), 4.24 (1H, m), 4.26 (2H, s), 7.08 (1H, dd, J=2.4,8.4 Hz), 7.20-7.40 (12H, m)

[0501] TSIMS(M/Z): 523(M+H)⁺

Example 162-Cyclohexyl-2,3-dihydro-6-[4-(3-phenyl-1-propyl)-piperazin-1-yl]-1H-isoindol-1-one

[0502] The title compound was obtained in the same manner as in step (f)of Example 1, except that 3-phenyl-1-propyl bromide was used instead ofbenzyl bromide.

[0503]¹H-NMR(CDCl₃) δ:1.18 (1H, m), 1.43-1.53 (4H, m), 1.67-1.75 (1H,m), 1.81-1.92 (6H, m), 2.41-2.47 (2H, m), 2.60-2.70 (6H, m), 3.24-3.28(4H, m), 4.25 (1H, m), 4.26 (2H, s), 7.11 (1H, dd, J=2.3, 8.4 Hz),7.16-7.21 (3H, m), 7.27-7.32 (3H, m), 7.36 (1H, d, J=2.3 Hz)

[0504] TSIMS(M/Z): 418(M+H)⁺

Example 176-[4-(Cinnamyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0505] The title compound was obtained in the same manner as in step (f)of Example 1, except that cinnamyl bromide was used instead of benzylbromide.

[0506]¹H-NMR(CDCl₃) δ:1.18 (1H, m), 1.43-1.64 (4H, m), 1.68-1.80 (1H,m), 1.84-1.87 (4H, m), 2.68-2.71 (4H, m), 3.22-3.30 (6H, m), 4.25 (1H,m), 4.27 (2H, s), 6.31 (1H, dt, J=6.7, 15.7 Hz), 6.57 (1H, d, J=15.7Hz), 7.12 (1H, dd, J=2.3, 8.4 Hz), 7.22-7.41 (7H, m)

[0507] TSIMS(M/Z): 416(M+H)⁺

Example 186-[4-(3-Chlorobenzyl)-piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0508] The title compound (14 mg) was obtained in the same manner as instep(f) of Example 1, except that the compound (30 mg) obtained in step(e) of Example 1 and 3-chlorobenzyl bromide (23 mg) were used.

[0509]¹H-NMR(CDCl₃) δ:1.46 (10H, m), 2.62 (4H, t, J=5.0 Hz), 3.15 (4H,t, J=5.0 Hz), 3.54 (2H, s), 4.20 (1H, m), 4.26 (2H, s), 7.10 (1H, dd,J=2.5, 8.4 Hz), 6.90 (2H, m), 7.12 (2H, m), 7.33 (4H, m)

[0510] FABMS(m/z): 424(M+H)⁺

Example 196-[4-(4-Bromobenzyl)-piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0511] The title compound (45 mg) was obtained in the same manner as instep (f) of Example 1, except that the compound(30 mg) obtained in step(e) of Example 1 and 4-bromobenzyl bromide (30 mg) were used.

[0512]¹H-NMR (CDCl₃) δ:1.60 (10H, m), 2.60 (4H, t, J=5.2 Hz), 3.24 (4H,t, J=5.2 Hz), 3.52 (2H, s), 4.22 (1H, m), 4.26 (2H, s), 7.09 (1H, dd,J=2.5, 8.4 Hz), 7.24 (2H, d, J=8.2 Hz), 7.30 (1H, d, J=8.4 Hz), 7.35(1H, d, J=2.5 Hz), 7.45(2H, d, J=8.2 Hz)

[0513] FABMS(m/z): 468(M+H)⁺

Example 206-[4-(2-Chlorobenzyl)-piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0514] The title compound (37 mg) was obtained in the same manner as instep (f) of Example 1, except that the compound (30 mg) obtained in step(e) of Example 1 and 2-chlorobenzyl bromide (23 mg) were used.

[0515]¹H-NMR(CDCl₃) δ:1.65 (10H, m), 2.70 (4H, t, J=4.9 Hz), 3.27 (4H,t, J=4.9 Hz), 3.70 (2H, s), 4.02 (1H, m), 4.02 (2H, s), 7.11 (1H, dd,J=1.9, 8.3 Hz), 7.30 (5H, m), 7.52 (1H, d, J=7.7 Hz)

[0516] FABMS(m/z): 424(M+H)⁺

Example 212-Cyclohexyl-2,3-dihydro-6-(4-triphenylmethyl-piperazin-1-yl)-1H-isoindol-1-one

[0517] The title compound (49 mg) was obtained in the same manner as instep (f) of Example 1, except that the compound (30 mg) obtained in step(e) of Example 1 and triphenylmethyl chloride (33 mg) were used.

[0518]¹H-NMR(CDCl₃) δ:1.57 (10H, m), 1.85 (4H, bs), 3.37 (4H, bs), 4.26(3H, bs), 7.05 (1H, dd, J=2.0, 7.1 Hz), 7.18 (2H, m), 7.30 (9H, m), 7.52(6H, m)

[0519] FABMS(m/z): 542(M+H)⁺

Example 222-Cyclohexyl-6-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0520] The title compound (32 mg) was obtained in the same manner as instep (f) of Example 1, except that the compound (30 mg) obtained in step(e) of Example 1 and 2-chlorobenzyl bromide (24 mg) were used.

[0521]¹H-NMR(CDCl₃) δ:1.67 (10H, m), 2.60 (4H, t, J=5.1 Hz), 3.25 (4H,t, J=5.1 Hz), 3.51 (2H, s), 4.27 (3H, m), 7.10 (1H, dd, J=2.3, 8.3 Hz),7.20 (1H, dd, J=2.0, 8.2 Hz), 7.31 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.3Hz), 7.41 (1H, d, J=8.2 Hz), 7.79 (1H, d, J=2.0 Hz)

[0522] EIMS(m/z): 457(M⁺)

Example 23 2-Cyclohexyl-6-[4-(4-biphenylmethyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0523] The title compound (43 mg) was obtained in the same manner as instep (f) of Example 1, except that the compound (30 mg) obtained instep(e) of Example land 4-(chloromethyl)biphenyl (24 mg) were used.

[0524]¹H-NMR(CDCl₃) δ:1.60 (10H, m), 2.67 (4H, t, J=4.7 Hz), 3.28 (4H,t, J=4.7 Hz), 3.63 (2H, s), 4.26 (1H, m), 4.27 (2H, s), 7.10 (1H, dd,J=2.3, 8.3 Hz), 7.30 (1H, d, J=8.3 Hz), 7.36 (2H, m), 7.45 (4H, m), 7.59(4H, m)

[0525] TSIMS(m/z): 466(M+H)⁺

Example 24 2-Cyclohexyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-5propyl)piperazin-1-yl]-5-fluoro-1H-isoindol-1-one

[0526] 2-Cyclohexyl-2,3-dihydro-5-fluoro-6-(piperazin-1-yl)-1H-isoindol-1-one was synthesized using 4-fluorophthalic anhydrideand cyclohexylamine according to step (a) and later steps of Example 1.In the same manner as in step (f) of Example 1, the title compound wasobtained from this compound and 3,3-diphenylpropyl bromide.

[0527]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.42-1.54 (4H, m), 1.65-1.75 (1H,m), 1.80-1.90 (4H, m), 2.26-2.39 (4H, m), 2.59-2.62 (4H, m), 3.11-3.14(4H, m), 4.02 (1H, t, J=7.2 Hz), 4.21 (1H, m), 4.26 (2H, s), 7.09 (1H,d, J=11.3 Hz), 7.12-7.22 (2H, m), 7.25-7.31 (8H, m), 7.42 (1H, d, J=7.9Hz)

[0528] ESIMS(M/Z): 512(M+H)⁺

Example 252-Cyclopropyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0529] 2-Cyclopropyl-2,3-dihydro-6-(piperazin-1-yl)-1H-isoindol-1-onewas synthesized from phthalic anhydride and cyclopropylamine in the samemanner as in Example 1. In the same manner as in step (f) of Example 1,the title compound was obtained from this compound and3,3-diphenylpropyl bromide.

[0530]¹H-NMR(CDCl₃) δ:0.81-0.94 (4H, m), 2.26-2.37 (4H, m), 2.56-2.60(4H, m), 2.89-2.95 (1H, m), 3.22-3.25 (4H, m), 4.02 (1H, t, J=7.1 Hz),4.22 (2H, s), 7.09 (1H, dd, J=2.4, 8.4 Hz), 7.15-7.20 (2H, m), 7.22-7.29(9H, m), 7.32 (1H, d, J=2.4 Hz)

[0531] TSIMS(M/Z): 452(M+H)⁺

Example 262-(4-Acetoxy)cyclohexyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one4

[0532]2-(4-Acetoxy)cyclohexyl-2,3-dihydro-6-(piperazin-1-yl)-1H-isoindol-1-onewas synthesized from phthalic anhydride and 4-hydroxycyclohexylaminehydrochloride in the same manner as in Example 1. In the same manner asin step (f) of Example 1, the title compound was obtained from thiscompound and 3,3-diphenylpropyl bromide.

[0533]¹H-NMR(CDCl₃) δ:7.34-7.25 (10H, m), 7.14-7.20 (2H, m), 7.10 (1H,dd, J=2.3, 8.4 Hz), 4.70 (11H, brs), 4.28 (1H, brs), 4.21 (2H, s), 4.01(1H, t, J=7.3 Hz), 3.25 (4H, t, J=4.7 Hz), 2.59 (4H, t, J=4.7 Hz), 2.31(4H, brs), 2.19 (2H, brs), 2.13 (3H, s), 1.90 (2H, brs), 1.60 (4H, brq)

[0534] TSIMS(m/z): 502(M+H)⁺

Example 272,3-Dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxy)cyclohexyl-1H-isoindol-1-one

[0535] The compound (72 mg) obtained in Example 26 was dissolved inmethanol (2 ml). Purified water (0.2 ml) and potassium carbonate (88 mg)were then added to the solution. The mixture was stirred at 30° C. for 2hr. MeOH was removed by distillation using an evaporator under thereduced pressure. A saturated aqueous ammonium chloride solution (3 ml)was then added to the residue, followed by separation with ethyl acetateand water. The ethyl acetate layer was washed with an aqueous sodiumchloride solution, was dried over magnesium sulfate, and thenconcentrated under the reduced pressure. The residue was purified bychromatography on silica gel (ethyl acetate:hexane=1:1) to give 34 mg of2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-hydroxy)cyclohexyl-1H-isoindol-1-one.

[0536]¹H-NMR(CDCl₃) δ:7.34-7.25 (10H, m), 7.14-7.20 (2H, m), 7.10 (1H,dd, J=2.3, 8.4 Hz), 4.20 (3H, brs), 4.01 (1H, t, J=7.3 Hz), 3.63 (1H,brs), 3.25 (4H, t, J=4.7 Hz), 2.59 (4H, t, J=4.7 Hz), 2.47 (1H, brs),2.33 (4H, brs), 2.09 (2H, brq), 1.87 (2H, brd), 1.54(4H, brq)

[0537] TSIMS(m/z): 510(M+H)⁺

Example 286-[4-(Benzyloxycarbonyl)piperazin-1-yl]-2-cyclo-hexyl-2,3-dihydro-1H-isoindol-1-one

[0538] Sodium hydrogencarbonate (67 mg, 0.8 mmol) and benzyloxycarbonylchloride (0.063 ml, 0.44 mmol) were added at 0° C. to a solution of thecompound (120 mg, 0.4 mol), obtained in step (e) of Example 1, indichloromethane (2 ml). The mixture was stirred for one day whilegradually raising the temperature from 0° C. to room temperature. A 0.1N aqueous citric acid solution was then added thereto. The mixture wasthen extracted with ethyl acetate. The extract was then washed withsaturated saline, and dried over anhydrous MgSO₄. The solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=1:1) to give 128 mg (74%) of the title compound.

[0539]¹H-NMR(CDCl₃) δ:1.12-1.25 (1H, m), 1.39-1.53 (4H, m), 1.69-1.79(1H, m), 1.80-1.87 (4H, m), 3.18-3.21 (4H, m), 3.66-3.70 (4H, m), 4.23(1H, m), 4.27 (2H, s), 5.17 (2H, s), 7.10 (1H, dd, J=2.4, 8.4 Hz),7.30-7.40 (7H, m)

[0540] ESIMS(M/Z): 434(M+H)⁺

Example 292-Cyclohexyl-2,3-dihydro-6-[4-(ethoxycarbonyl)-piperazin-1-yl]-1H-isoindol-1-one

[0541] In the same manner as in Example 28, the title compound wasprepared from the compound obtained in step (e) of Example 1 andethoxycarbonyl chloride.

[0542]¹H-NMR(CDCl₃) δ:1.17-1.19 (1H, m), 1.29 (3H, t, J=7.1 Hz),1.43-1.50 (4H, m), 1.70-1.75 (1H, m), 1.82-1.87 (4H, m), 3.17-3.21 (4H,m), 3.63-3.66 (4H, m), 4.18 (2H, q, J=7.1 Hz), 4.24 (1H, m), 4.28 (2H,s), 7.11 (1H, dd, J=2.3, 8.3 Hz), 7.33 (1H, d, J=8.3 Hz), 7.36 (1H, d,J=2.3 Hz)

[0543] TSIMS(M/Z): 372(M+H)⁺

Example 306-[4-(t-Butoxycarbonyl)piperazin-1-yl]-2-cyclo-hexyl-2,3-dihydro-1H-isoindol-1-one

[0544] In the same manner as in Example 28, the title compound wasprepared from the compound obtained in step (e) of Example 1 anddi-t-butyl dicarbonate.

[0545]¹H-NMR(CDCl₃) δ:1.17-1.20 (1H, m), 1.43-1.58 (4H, m), 1.48 (9H,s), 1.69-1.77 (1H, m), 1.81-1.93 (4H, m), 3.16-3.19 (4H, m), 3.58-3.61(4H, m), 4.24 (1H, m), 4.27 (2H, s), 7.11 (1H, dd, J=2.4, 8.4 Hz), 7.33(1H, d, J=8.4 Hz), 7.36 (1H, d, J=2.4 Hz)

[0546] TSIMS(M/Z): 400(M+H)⁺

Example 316-[4-(Benzoyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0547] In the same manner as in Example 28, the title compound wasprepared from the compound obtained in step (e) of Example 1 and benzoylchloride.

[0548]¹H-NMR(CDCl₃) δ:1.18-1.26 (1H, m), 1.44-1.54 (4H, m), 1.70-1.81(1H, m),1.82-1.92 (4H, m),3.16-3.33 (4H, m),3.59-3.69 (2H, m), 3.90-3.99(2H, m), 4.24 (1H, m), 4.29 (2H, s), 7.12 (1H, dd, J=2.3, 8.6 Hz), 7.35(1H, d, J=8.6 Hz), 7.37 (1H, d, J=2.3 Hz), 7.45(5H, s)

[0549] ESIMS(M/Z): 404(M+H)⁺

Example 322-Cyclohexyl-2,3-dihydro-6-[4-(pivaloyl)piperazin-1-yl]-1H-isoindol-1-one

[0550] In the same manner as in Example 28, the title compound wasprepared from the compound obtained in step(e) of Example 1 and pivaloylchloride.

[0551]¹H-NMR(CDCl₃) δ:7.34 (1H, d, J=2.2 Hz), 7.30 (2H, d, J=8.3 Hz),7.18 (1H, dd, J=2.2, 8.3 Hz), 4.25 (2H, s), 4.20 (1H, Brs), 3.80 (4H, t,J=4.9 Hz), 3.18 (4H, t, J=4.9 Hz), 1.83-1.18 (19H, m)

[0552] ESMS(m/z): 384(M+H)⁺

Example 336-[4-(Benzhydryloxycarbonyl)piperazin-1-yl]-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0553] In the same manner as in Example 28, the title compound wasprepared from the compound obtained in step (e) of Example 1 andbenzhydryloxycarbonyl azide.

[0554]¹H-NMR(CDCl₃)δ:1.18 (1H, m), 1.40-1.54 (4H, m), 1.70-1.81 (1H, m),1.84-1.87 (4H, m), 3.20-3.23 (4H, m), 3.64-3.84 (4H, m), 4.23 (1H, m),4.27 (2H, s), 6.85 (1H, s), 7.11 (1H, dd, J=2.4, 8.4 Hz), 7.25-7.36(12H, m)

[0555] TSIMS(M/Z): 510(M+H)⁺

Example 342-Cyclohexyl-6-[4-(4-methoxybenzyloxycarbonyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0556] 4-Methoxybenzyl-S-(4,6-dimethylpyrimidin-2-yl)-thiocarbonate (34mg) was added to a solution of the compound (30 mg) obtained in step (e)of Example 1 in methylene chloride (1 ml). The mixture was stirred atroom temperature for 20 min. Water was added to the reaction solution.The mixture was then extracted with ethyl acetate. The extract was driedover anhydrous magnesium sulfate. The solvent was then removed bydistillation. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:1) to give the title compound (45mg).

[0557]¹H-NMR(CDCl₃) δ:1.59 (10H, m), 3.16 (4H, bs), 3.67 (4H, bs), 3.82(3H, s), 4.27 (3H, m), 5.10 (2H, s), 6.90 (2H, m), 7.12 (2H, m), 7.33(4H, m)

[0558] ESIMS(m/z): 464(M+H)⁺

Example 352-Cyclohexyl-2,3-dihydro-6-[4-(3,5-dimethoxy-4-hydroxybenzoyl)piperazin-1-yl]-1H-isoindol-1-one

[0559] A solution of syringic acid (20 mg) in dry DMF (2 ml) was cooledto 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(WSCI) and 1-hydroxybenztriazole hydrate (HOBt) were added thereto inthat order. The mixture was stirred at 0° C. for one hr. The compound(30 mg) obtained in step (e) of Example 1 and triethylamine were addedthereto in that order. The mixture was stirred at 0° C. for one hr, andthen stirred at room temperature overnight. A saturated aqueous ammoniumchloride solution(5 ml) was added thereto, followed by separation withethyl acetate and water. The ethyl acetate layer was washed with anaqueous sodium chloride solution, dried over magnesium sulfate, and thenconcentrated under the reduced pressure. The residue was purified bychromatography on silica gel (chloroform:methanol=20:1) to give 42 mg ofthe title compound.

[0560]¹H-NMR(CDCl₃) δ:8.03 (2H, s), 7.35-7.13 (2H, m), 6.72 (2H, d,J=2.2 Hz), 5.80 (1H, s), 4.29 (2H, s), 4.23 (1H, Brs), 3.93 (6H, s),2.97 (4H, s), 2.89 (4H, s), 1.83-1.18 (10H, m)

[0561] ESMS(m/z): 480(M+H)⁺

Example 362-cyclohexyl-2,3-dihydro-6-[4-(pyridine-3-carbonyl)piperazin-1-yl]-1H-isoindol-1-one

[0562] In the same manner as in Example 35, the title compound wasprepared from the compound obtained in step (e) of Example 1 andnicotinic acid.

[0563]¹H-NMR(CDCl₃) δ:8.72 (2H, m), 7.81 (1H, td, J=2.1, 7.7 Hz), 7.41(3H, m), 7.12 (1H, dd, J=2.3, 8.3 Hz), 4.29 (2H, S), 4.24 (1H, Brs),3.80 (4H, brd), 3.28 (4H, brd), 1.83-1.18 (10H, m)

[0564] ESMS(m/z): 405(M+H)⁺

Example 372-cyclohexyl-2,3-dihydro-6-[4-diphenylacetyl-piperazin-1-yl]-1H-isoindol-1-one

[0565] In the same manner as in Example 35, the title compound wasprepared from the compound obtained in step (e) of Example 1 anddiphenyl acetate.

[0566]¹H-NMR(CDCl₃) δ:7.34-7.22 (6H, m), 7.19 (2H, t, J=8.0 Hz), 7.07(1H, dd, J=2.2, 8.3 Hz), 4.26 (4H, m), 3.23 (4H, t, J=4.7 Hz), 2.58 (4H,t, J=4.7 Hz), 1.83-1.18 (10H, m)

[0567] EIMS(m/z): 465(M⁺)

Example 382-Cyclohexyl-2,3-dihydro-6-[4-(2,2-diphenylethyl)-piperazin-1-yl]-1H-isoindol-1-one

[0568] Diphenylacetaldehyde (40 mg) was added to a solution of thecompound (60 mg), obtained in step (e) of Example 1, in1,2-dichloroethane (2 ml). The mixture was stirred at 0° C. Sodium borontriacetoxyhydride (44 mg) was added to the reaction solution, followedby stirring at 0° C. for one hr. The mixture was then stirred at roomtemperature overnight. A saturated aqueous ammonium chloride solution (5ml) was then added thereto, followed by separation with ethyl acetateand water. The ethyl acetate layer was washed with an aqueous sodiumchloride solution, dried over magnesium sulfate, and then concentratedunder the reduced pressure . The residue was purified by chromatographyon silica gel ( ethyl acetate:hexane=1:1) to give 76 mg of the titlecompound.

[0569]¹H-NMR(CDCl₃) δ:7.34-7.25 (9H, m), 7.23-7.16 (2H, m), 7.05 (2H,dd, J=2.0, 8.0 Hz), 4.23 (5H, m), 3.15 (4H, t, J=4.7 Hz) 2.65 (4H, t,J=4.7 Hz), 2.06 (2H, d, J=4.9 Hz), 1.83-1.18 (10H, m)

[0570] FABMS(m/z): 480(M+H)⁺

Example 392-Cyclohexyl-2,3-dihydro-6-[4-(4-hydroxyphenyl)-methylpiperazin-1-yl]-1H-isoindol-1-one

[0571] In the same manner as in Example 38, the title compound wasprepared from the compound obtained in step (e) of Example 1 and4-hydroxybenzaldehyde.

[0572]¹H-NMR(CDCl₃) δ: 1.16 (1H, m), 1.45 (4H, m), 1.71 (1H, br.d), 1.86(4H, m), 2.58 (4H, m), 3.19 (4H, m), 3.47 (2H, s), 4.23 (1H, m), 4.27(2H, s), 6.82 (2H, d, J=8.7), 7.09 (1H, dd, J=2.2, 8.3), 7.16 (2H, d,J=8.7), 7.29 (1H, d, J=8.3), 7.34 (1H, dd, J=2.2, 8.3)

[0573] FABMS(m/z): 406(M+H)⁺

Example 402-Cyclohexyl-2,3-dihydro-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-1H-isoindol-1-one

[0574] In the same manner as in Example 38, the title compound wasprepared from the compound obtained in step (e) of Example 1 and4,4-diphenylbutylaldehyde.

[0575]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.38-1.60 (6H, m), 1.69-1.77 (1H,m), 1.78-1.86 (4H, m), 2.05-2.13 (2H, m), 2.41 (2H, t, J=7.5 Hz),2.53-2.56 (4H, m), 3.20-3.24 (4H, m), 3.91 (1H, t, J=7.9 Hz), 4.24 (1H,m), 4.26 (2H, s), 7.09 (1H, dd, J=2.4, 8.3 Hz), 7.14-7.19 (2H, m),7.20-7.31 (9H, m), 7.34 (1H, d, J=2.4 Hz)

[0576] TSIMS(M/Z): 508(M+H)⁺

Example 412-Cyclohexyl-6-{4-[3,3-bis(4-methoxyphenyl)-1-propyl]-piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one

[0577] (a) 10% Pd-C (20 mg) was added to a solution of3,3-bis(4-methoxyphenyl)-propenenitrile (50 mg), synthesized by theprocess described in a literature J. Med. Chem., 32, 1820 (1989), indioxane (5 ml), followed by hydrogenation for 2 hr. Pd-C was removed byfiltration through Celite. The solvent was then removed by distillationto give 3,3-bis(4-methoxyphenyl)-propanenitrile (38 mg).

[0578]¹H-NMR(CDCl₃) δ:2.98 (2H, d, J=7.7 Hz), 3.79 (6H, s), 4.30 (1H, t,J=7.7 Hz), 6.87 (4H, d, J=8.6 Hz), 7.15 (4H, d, J=8.6 Hz)

[0579] EIMS(m/z): 267(M⁺) (b) A 1.5 M toluene solution (0.37 ml) ofDIBAL-H was added to a solution of the compound (100 mg) obtained instep (a) in toluene (10 ml) under cooling at −40° C. The mixture wasstirred for 2.5 hr. A 1 N aqueous HCl solution was added to the reactionsolution. The mixture was extracted with ethyl acetate. The extract wasdried over anhydrous magnesium sulfate. The solvent was then removed bydistillation to give 3,3-bis(4-methoxyphenyl)-propanaldehyde.

[0580]¹H-NMR(CDCl₃) δ:3.10 (2H, dd, J=1.9, 7.7 Hz), 3.79 (6H, s), 4.54(1H, t, J=7.7 Hz), 6.87 (4H, d, J=8.8 Hz), 7.14 (4H, d, J=8.8 Hz), 9.73(1H, t, J=1.9)

[0581] (c) In the same manner as in Example 38, the title compound (52mg) was prepared from the compound (47 mg) obtained in step (e) ofExample 1 and the compound (110 mg) obtained in step (b).

[0582]¹H-NMR(CDCl₃) δ:1.47 (10H, m), 2.26 (4H, m), 2.59 (4H, t, J=4.6Hz), 3.25 (4H, t, J=4.6 Hz), 3.78 (6H, s), 4.26 (1H, m), 4.27 (2H, s),6.83 (4H, d, J=8.6 Hz), 8.78 (7H, m)

[0583] FABMS(m/z): 554(M+H)⁺

Example 422-Cyclohexyl-6-{4-[3,3-bis(4-chlorophenyl)-1-propyl]-piperazin-1-yl}-2,3-dihydro-1H-isoindol-1-one

[0584] (a) Diethyl cyanomethylphosphonate (1.95 g) was added to asolution of sodium (345 mg) dissolved, under cooling in an ice bath, inethanol (30 ml). The mixture was heated under reflux for one hr. Thereaction solution was concentrated under the reduced pressure. Water wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous magnesium sulfate. The solvent wasthen removed by distillation. The residue was purified by chromatographyon silica gel (hexane:ethyl acetate=9:1) to give3,3-bis(4-chlorophenyl)-propenenitrile (2.95 g).

[0585]¹H-NMR(CDCl₃) δ:5.73 (1H, s), 7.23 (4H, d, J=8.8 Hz), 7.45 (4H, d,J=8.8 Hz)

[0586] TSIMS (m/z): 275(M+H)⁺

[0587] (b) Sodium boron hydride (756 mg) was added to a solution of thecompound (550 mg), obtained in step (a) just above, in ethanol (20 ml)under cooling in an ice bath. The mixture was then heated under refluxfor 1.5 hr. The reaction solution was concentrated under the reducedpressure. Water was added to the residue. The mixture was extracted withethyl acetate, and then dried over anhydrous magnesium sulfate. Thesolvent was then removed by distillation. The residue was purified bychromatography on silica gel (hexane:ethyl acetate=9:1) to give3,3-bis(4-chlorophenyl)-propanenitrile (311 mg).

[0588]¹H-NMR(CDCl₃) δ:3.00 (2H, d, J=7.6 Hz), 4.35 (1H, t, J=7.6 Hz),7.15 (4H, d, J=8.4 Hz), 7.33 (4H, d, J=8.4 Hz)

[0589] EIMS(m/z): 277(M+H)⁺

[0590] (c) In the same manner as in Example 41,3,3-bis(4-chlorophenyl)-propanaldehyde was prepared from a solution ofthe compound (100 mg), obtained in step (b), in tetrahydrofuran (10 ml).

[0591]¹H-NMR(CDCl₃) δ:3.15 (2H, dd, J=1.6, 7.7 Hz), 4.59 (1H, t, J=7.7Hz), 7.14 (4H, d, J=8.3 Hz), 7.28 (4H, d, J=8.3 Hz)

[0592] EIMS(m/z): 278(M⁺)

[0593] (d) In the same manner as in Example 38, the title compound (52mg) was prepared from the compound (69 mg) obtained in step (e) ofExample 1 and the compound (78 mg) obtained in step (c) just above.

[0594]¹H-NMR (CDCl₃) δ:1.46 (4H, m), 1.85 (6H, m), 2.30 (4H, m), 2.57(4H, t, J=4.8 Hz), 3.24 (4H, t, J=4.8 Hz), 4.23 (1H, m), 4.26 (2H, s),7.10 (1H, dd, J=2.2, 8.3 Hz), 7.15 (4H, d, J=8.5 Hz), 7.26 (4H, d, J=8.5Hz), 7.30 (1H, d, J=8.3 Hz), 7.35 (1H, d, J=2.2 Hz)

[0595] PBCMS (m/z): 562(M+H)⁺

Example 432-Cyclohexyl-2,3-dihydro-5-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0596] (a) In the same manner as in step (a) of Example1,2-cyclohexyl-5-nitrophthalimide was synthesized from 4-nitrophthalicanhydride and cyclohexylamine.

[0597]¹H-NMR(CDCl₃) δ:1.19-1.49 (3H, m), 1.61-1.85 (3H, m), 1.88-2.08(2H, m), 2.14-2.27 (2H, m), 4.11-4.21 (1H, m), 8.01 (1H, d, J=8.1 Hz),8.58 (1H, dd, J=2.0, 8.1 Hz), 8.64 (1H, d, J=2.0 Hz)

[0598] EIMS(M/Z): 274(M⁺)

[0599] (b) The compound obtained in step (a) just above was reduced inthe same manner as in step (b) of Example 1 to obtain an about 4:1mixture (92%) of5-acetylamino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one and6-acetylamino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one.

[0600] These position isomers cannot be isolated by columnchromatography on silica gel. Therefore, after the formation of theseisomers was confirmed by ¹H-NMR and ESIMS, the following reaction wascarried out. Specifically, concentrated hydrochloric acid (15 ml) wasadded at room temperature to a solution of the mixture of positionisomers (0.953 g, 3.5 mmol) in 1,4-dioxane (15 ml). The mixture wasstirred at 100° C. for one hr. The temperature of the reaction solutionwas returned to room temperature. The solvent was then removed bydistillation under the reduced pressure. A saturated aqueous NaHCO₃solution was then added to the residue. The mixture was extracted withethyl acetate. The extract was washed with saturated saline, and thendried over anhydrous MgSO₄. The solvent was then removed by distillationunder the reduced pressure. The residue was purified by columnchromatography on ODS (methanol:water=3:1) to give 513 mg (64%) of5-amino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one and 113 mg (14%) of6-amino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one.

[0601]¹H-NMR(CDCl₃)δ:1.16 (1H, m), 1.41-1.48 (4H, m), 1.71-1.78 (1H, m),1.79-1.90 (4H, m), 4.00 (2H, brs), 4.19 (1H, m), 4.23 (2H, s), 6.67-6.71(2H, m), 7.62 (1H, d, J=8.0 Hz)

[0602] TSIMS(M/Z): 231(M+H)⁺

[0603] (c) In the same manner as in step (e) of Example 1,2-cyclohexyl-2,3-dihydro-5-(piperazin-1-yl)-1H-isoindol-1-one wassynthesized from 5-amino-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-oneobtained in step (b) just above and bis(2-chloroethyl)aminehydrochloride.

[0604]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.42-1.53 (4H, m), 1.71-1.80 (1H,m), 1.84-1.86 (4H, m), 3.03-3.07 (4H, m), 3.24-3.27 (4H, m), 4.21 (1H,m), 4.27 (2H, s), 6.90 (1H, s), 6.99 (1H, dd, J=2.1, 8.6 Hz), 7.70 (1H,d, J=8.6 Hz)

[0605] ESIMS(M/Z): 300(M+H)⁺

[0606] (d) In the same manner as in step (f) of Example 1, the titlecompound was prepared from the compound obtained in step (c) just aboveand 3,3-diphenylpropyl bromide.

[0607]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.42-1.52 (4H, m), 1.67-1.79 (1H,m), 1.80-1.90 (4H, m), 2.27-2.38 (4H, m), 2.56-2.59 (4H, m), 3.27-3.30(4H, m), 4.02 (1H, t, J=7.2 Hz), 4.20 (1H, m), 4.26 (2H, s), 6.88 (1H,s), 6.97 (1H, dd, J=1.9, 8.6 Hz), 7.15-7.24 (2H, m), 7.25-7.31 (8H, m),7.69 (1H, d, J=8.6 Hz)

[0608] EIMS(M/Z): 493(M⁺)

Example 44 2-Cyclohexyl-2,3-dihydro-5-[4-(trans,trans-farnesyl)piperazin-1-yl]-1H-isoindol-1-one

[0609] In the same manner as in step (f) of Example 1, the titlecompound was obtained from the compound obtained in step (c) of Example43 and trans,trans-farnesyl bromide.

[0610]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.38-1.58 (4H, m), 1.60 (6H, s),1.67 (3H, s), 1.68 (3H, s), 1.73-1.78 (1H, m), 1.79-1.85 (4H, m),1.95-2.01 (2H, m), 2.03-2.17 (6H, m), 2.60-2.63 (4H, m), 3.05 (2H, d,J=6.9 Hz), 3.29-3.32 (4H, m), 4.20 (1H, m), 4.27 (2H, s), 5.07-5.12 (2H,m), 5.28-5.32 (1H, m), 6.89 (1H, br s), 6.98 (1H, dd, J=2.1, 8.6 Hz),7.70 (1H, d, J=8.6 Hz)

[0611] EIMS(M/Z): 503(M⁺)

Example 456-[4-(t-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0612] N-Chlorosuccinimide (87 mg, 0.65 mmol) and2,2-azobisisobutyronitrile (4 mg, 0.025 mmol) were added at roomtemperature to a solution of the compound (200 mg, 0.5 mmol), obtainedin Example 30, in carbon tetrachloride (5 ml). The mixture was stirredat 90° C. for 4.5 hr. The temperature of the system was returned to roomtemperature. The solvent was then removed by distillation under thereduced pressure. The residue was diluted with diethyl ether. Thediluted solution was washed with water, and then dried over anhydrousMgSO₄. The solvent was then removed by distillation under the reducedpressure. The residue was purified by preparative TLC (chloroform:ethylacetate=20:1) (number of times of development: three) to give 89 mg(41%) of 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one and 54 mg (25%) of6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclo-hexyl-2,3-dihydro-1H-isoindol-1-one.

[0613]¹H-NMR(CDCl₃) δ:1.18 (1H, m), 1.42-1.63 (13H, m), 1.69-1.77 (1H,m), 1.80-1.92 (4H, m), 3.00-3.04 (4H, m), 3.61-3.65 (4H, m), 4.23 (1H,m), 4.25 (2H, s), 7.16 (1H, d, J=8.1 Hz), 7.28 (1H, d, J=8.1 Hz)

[0614] TSIMS(M/Z): 434(M+H)⁺

Example 466-[4-(t-Butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one

[0615] The title compound was obtained in the same manner as in Example45.

[0616]¹H-NMR(CDCl₃) δ:1.18 (1H, m), 1.43-1.61 (13H, m), 1.69-1.77 (1H,m),1.81-1.91 (4H, m),2.99-3.02 (4H, m),3.60-3.63 (4H, m), 4.22 (1H, m),4.28 (2H, s), 7.47 (1H, s), 7.50 (1H, s)

[0617] TSIMS(M/Z): 434(M+H)⁺

Example 477-Chloro-2-cyclohexyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0618] Trifluoroacetic acid (0.125 ml) was added at 0° C. to a solutionof6-[4-(t-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one(43 mg, 0.1 mmol), obtained in Example 45, in dichloromethane (1 ml).The mixture was stirred at room temperature for 2 hr. The reactionsolution was concentrated under the reduced pressure. A saturatedaqueous NaHCO₃ solution was then added thereto. The mixture wasextracted with chloroform. The extract was washed with saturated saline,and then dried over anhydrous MgSO₄. The solvent was then removed bydistillation under the reduced pressure. Potassium carbonate (28 mg, 0.2mmol) and 3,3-diphenylpropyl bromide (30 mg, 0.11 mmol) were added at 0°C. to a solution of the crude product, thus obtained, inN,N-dimethylformamide (1 ml). The mixture was stirred at 50° C. for 5hr. The temperature of the system was then returned to room temperature,and a 0.1 N aqueous citric acid solution was added thereto. The mixturewas extracted with ethyl acetate, washed with saturated saline, and thendried over anhydrous MgSO₄. The solvent was then removed by distillationunder the reduced pressure. The residue was purified by preparative TLC(chloroform:methanol=30:1) to give 17 mg (32%) of the title compound.

[0619]¹H-NMR(CDCl₃) δ:1.17 (1H, m), 1.42-1.52 (4H, m), 1.68-1.80 (1H,m), 1.81-1.87 (4H, m), 2.28-2.40 (4H, m), 2.60-2.69 (4H, m), 3.04-3.12(4H, m), 4.02 (1H, t, J=7.5 Hz), 4.19-4.24 (3H, m), 7.15-7.21 (3H, m),7.25-7.31 (9H, m)

[0620] TSIMS(M/Z): 528(M+H)⁺

Example 485-Chloro-2-cyclohexyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0621] In the same manner as in Example 47, the title compound wasprepared from6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-oneobtained in Example 45 and 3,3-diphenylpropyl bromide.

[0622]¹H-NMR(CDCl₃) δ:1.18 (1H, m), 1.41-1.51 (4H, n), 1.70-1.75 (1H,m), 1.82-1.89 (4H, m), 2.27-2.39 (4H, m), 2.58-2.65 (4H, m), 3.07-3.13(4H, m), 4.02 (1H, t, J=7.4 Hz), 4.05-4.26 (3H, m), 7.17-7.23 (2H, m),7.25-7.36 (8H, m), 7.44 (1H, s), 7.52 (1H, s)

[0623] TSIMS(M/Z): 528(M+H)⁺

Example 496-[4-t-butoxycarbonylpiperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0624] In the same manner as in step (b) or later steps of Example 1 andExample 30, the title compound was obtained using phthalimide.

[0625]¹H-NMR(CDCl₃) δ:7.38-7.35 (2H, m), 7.17 (1H, dd, J=2.2, 8.6), 4.70(1H, brs), 4.39 (2H, s), 3.59 (4H, t, J=4.8 Hz), 3.18 (4H, t, J=4.8 Hz),1.77 (1H, s), 1.49 (9H, s)

[0626] ESIMS(m/z): 318(M+H)⁺

Example 502,3-Dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0627] In the same manner as in Example 47, the title compound wasprepared from the compound obtained in Example 49.

[0628]¹H-NMR(CDCl₃) δ:2.25-2.38 (4H, m), 2.56-2.60 (4H, m), 3.23-3.27(4H, m), 4.02 (1H, t, J=7.1 Hz), 4.36 (2H, s), 6.56 (1H, brd), 7.14-7.56(10H, m)

[0629] EIMS(m/z): 411(M⁺)

Example 512-Benzyl-2,3-dihydro-6-[4-(t-butoxycarbonyl)-piperazin-1-yl]-1H-isoindol-1-one

[0630] Potassium carbonate (88 mg), sodium hydroxide (44 mg),tetrabutylaummonium hydrogen sulfate (11 mg), and benzyl bromide (81 mg)were added to a solution of the compound (100 mg), obtained in Example49, in toluene (2 ml). The mixture was stirred at 80° C. overnight. Themixture was then cooled to room temperature. A saturated aqueousammonium chloride solution (5 ml) was then added thereto, followed byseparation with ethyl acetate and water. The ethyl acetate layer waswashed with an aqueous sodium chloride solution, dried over magnesiumsulfate, and then concentrated under the reduced pressure. The residuewas purified by chromatography on silica gel (ethyl acetate:hexane=1:1)to give 111 mg of the title compound.

[0631]¹H-NMR(CDCl₃) δ:7.40 (1H, d, J=2.2 Hz), 7.31 (1H, d, J=3.3), 7.11(1H, dd, J=2.2, 3.3 Hz), 4.80 (2H, s), 4.21 (2H, s), 3.61 (4H, t,J=4.9), 3.19 (4H, t, J=4.9), 1.50 (9H, s)

[0632] TSIMS(m/z): 408(M+H)⁺

Example 522-Benzyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-1H-isoindol-1-one

[0633] (a) Concentrated hydrochloric acid (0.5 ml) was added to asolution of the compound (90 mg), obtained in Example 51, in ethylacetate(2 ml). The mixture was stirred at room temperature for 45 min.Ethyl acetate and purified water were then added thereto, followed byseparation. The aqueous layer was concentrated under the reducedpressure to give 80 mg of 2-benzyl-2,3-dihydro-6-piperazine-1H-isoindol-1-one dihydrochloride.

[0634]¹H-NMR(D₂O) δ:6.98-6.87 (3H, m), 4.24 (2H, s), 3.64 (2H, s), 3.32(8H, brs)

[0635] (b) In the same manner as in step (f) of Example 1, the titlecompound was prepared from the compound obtained in step (a) just aboveand 3,3-diphenylpropyl bromide.

[0636]¹H-NMR(CDCl₃) δ: 7.45-7.08 (18H, m), 4.73 (2H, s), 4.17 (2H, s),4.02 (1H, t, J=7.3 Hz), 3.26 (4H, t, J=5.0 Hz), 2.59 (4H, t, J=5.0 Hz),2.32 (4H, m)

[0637] TSIMS(m/z): 502(M+H)⁺

Example 532-(4-Bromo)benzyl-6-(4-t-butoxycarbonylpiperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one

[0638] The title compound was obtained in the same manner as in Example51, except that 4-bromo benzyl bromide was used instead of benzylbromide.

[0639]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 4.73 (2H, sHz), 4.17 (2H, s), 4.02 (1H, t,J=7.3 Hz), 3.58 (4H, t, J=5.0 Hz), 3.17 (4H, t, J=5.0 Hz), 2.32 (4H, m),1.49 (9H, S)

[0640] TSIMS(m/z): 487(M+H)⁺

Example 542-(4-Bromo)benzyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0641] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 53.

[0642]¹H-NMR(CDCl₃) δ:7.45-7.08 (17H, m), 4.73 (2H, s), 4.17 (2H, s),4.02 (1H, t, J=7.3 Hz), 3.26 (4H, t, J=5.0 Hz), 2.59 (4H, t, J=5.0 Hz),2.32 (4H, m)

[0643] TSIMS(m/z): 582(M+H)⁺

Example 556-(4-t-Butoxycarbonylpiperazin-1-yl)-2-(4-chloro)-benzyl-2,3-dihydro-1H-isoindol-1-one

[0644] In the same manner as in Example 51, the title compound wasobtained from 4-chlorobenzyl chloride.

[0645]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 4.73 (2H, sHz), 4.17 (2H, s), 4.02 (1H, t,J=7.3 Hz), 3.58 (4H, t, J=5.0 Hz), 3.17 (4H, t, J=5.0 Hz), 2.32 (4H, m),1.49 (9H, s)

[0646] TSIMS(m/z): 442(M+H)⁺

Example 562-(4-Chloro)benzyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0647] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 55.

[0648]¹H-NMR(CDCl₃) δ:7.45-7.08 (17H, m), 4.73 (2H, s), 4.17 (2H, s),4.02 (1H, t, J=7.3 Hz), 3.26 (4H, t, J=5.0 Hz), 2.59 (4H, t, J=5.0 Hz),2.32 (4H, m)

[0649] TSIMS(m/z): 537(M+H)⁺

Example 576-(4-t-Butoxycarbonylpiperazin-1-yl)-2,3-dihydro-2-(4-methoxy)benzyl-1H-isoindol-1-one

[0650] The title compound was obtained in the same manner as in Example51, except that 4-methoxybenzyl chloride was used instead of benzylbromide.

[0651]¹H-NMR(CDCl₃) δ:7.32 (1H, d, J=2.4 Hz), 7.17 (2H, m), 7.02 (1H,dd, J=2.4, 8.3 Hz), 6.78 (2H, d, J=8.3 Hz), 4.66 (2H, s), 4.09 (2H, s),3.72 (3H, s), 3.52 (4H, t, J=5.0 Hz), 3.11 (4H, t, J=5.0 Hz), 1.42 (9H,s)

[0652] ESIMS(m/z): 438(M+H)⁺

Example 582,3-Dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-methoxy)benzyl-1H-isoindol-1-one

[0653] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 57.

[0654]¹H-NMR(CDCl₃) δ:7.39 (1H, d, J=2.4 Hz),7.24-7.20 (13H, m), 7.07(1H, dd, J=2.4, 8.3 Hz), 4.73 (2H, s), 4.13 (2H, s), 4.02 (1H, t, J=7.3Hz), 3.79 (3H, s), 3.24 (4H, t, J=5.0 Hz), 2.57 (4H, t, J=5.0 Hz), 2.30(4H, m)

[0655] TSIMS(m/z): 537(M+H)⁺

Example 596-(4-t-Butoxycarbonylpiperazin-1-yl)-2-cyclopropyl-methyl-2,3-dihydro-1H-isoindol-1-one

[0656] The title compound was obtained in the same manner as in Example51, except that cyclopropylmethyl bromide was used instead of benzylbromide.

[0657]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 4.27 (2H, s), 4.01 (1H, t, J=7.5 Hz), 3.58(4H, t, J=4.8 Hz), 3.50 (2H, d, J=7.4 Hz), 3.17 (4H, t, J=4.8 Hz), 1.49(9H, s), 1.25-1.11 (5H, m)

[0658] TSIMS(m/z): 372(M+H)⁺

Example 602-Cyclopropylmethyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0659] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 59.

[0660]¹H-NMR(CDCl₃) δ:7.33 (1H, d, J=2.2 Hz), 7.30-7.15 (11H, m), 7.09(1H, dd, J=2.2, 8.3 Hz), 4.27 (2H, s), 4.01 (1H, t, J=7.5 Hz), 3.50 (2H,d, J=7.4 Hz), 3.24 (4H, t, J=5.0 Hz), 2.57 (4H, t, J=5.0 Hz), 2.32 (4H,m), 1.25-1.11 (5H, m)

[0661] TSIMS(m/z): 466(M+H)⁺

Example 61

[0662]6-(4-t-Butoxycarbonylpiperazin-1-yl)-2-cyclohexyl-methyl-2,3-dihydro-1H-isoindol-1-one

[0663] In the same manner as in Example 51, the title compound wasobtained from cyclohexylmethyl bromide.

[0664]¹H-NMR(CDCl₃) δ: 7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 4.30 (2H, s), 3.58 (4H, t, J=5.0 Hz), 3.43(2H, d, J=7.1 Hz), 3.17 (4H, t, J=5.0 Hz), 1.82-1.62 (4H, m), 1.48 (9H,s), 1.19 (11H, m)

[0665] TSIMS(m/z): 508(M+H)⁺

Example 622-Cyclohexylmethyl-2,3-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0666] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 61.

[0667]¹H-NMR(CDCl₃) δ:7.33 (1H, d, J=2.2 Hz), 7.30-7.15 (11H, m), 7.09(1H, dd, J=2.2, 8.3 Hz), 4.27 (2H, s), 4.01 (1H, t, J=7.5 Hz), 3.42 (2H,d, J=7.4 Hz), 3.24 (4H, t, J=5.0 Hz), 2.57 (4H, t, J=5.0 Hz), 2.32 (4H,m), 1.25-1.02 (11H, m)

[0668] TSIMS(m/z): 508(M+H)⁺

Example 636-[4-t-Butoxycarbonylpiperazin-1-yl]-2,3-dihydro-2-methyl-1H-isoindol-1-one

[0669] In the same manner as in Example 51, the title compound wasobtained from methyl iodide.

[0670]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 3.60 (4H, t, J=5.0 Hz), 3.20 (4H, m), 1.49(9H, S)

[0671] TSIMS(m/z): 332(M+H)⁺

Example 642,3-Dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-methyl-1H-isoindol-1-one

[0672] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 63.

[0673]¹H-NMR(CDCl₃) δ:7.34-7.25 (10H, m), 7.14-7.20 (2H, m), 7.10 (1H,dd, J=2.3, 8.4 Hz), 4.20 (2H, s), 4.00 (1H, t, J=7.3 Hz), 3.25 (4H, t,J=4.7 Hz), 3.18 (3H, s), 2.57 (4H, t, J=4.7 Hz), 2.32 (4H, brs), 1.70(2H, brs)

[0674] TSIMS(m/z): 426(M+H)⁺

Example 656-(4-t-Butoxycarbonylpiperazin-1-yl)-2,3-dihydro-2-(4-nitro-benzyl)-1H-isoindol-1-one

[0675] In the same manner as in Example 51, the title compound wasobtained from 4-nitro-benzyl bromide.

[0676]¹H-NMR(CDCl₃) δ:7.44 (2H, td, J=6.5, 2.3 Hz), 7.39 (1H, d, J=2.3Hz), 7.29 (1H, d, J=4.7 Hz), 7.16 (2H, d, J=8.4 Hz), 7.11 (1H, dd,J=8.4, 2.3 Hz), 4.74 (2H, s), 3.60 (4H, t, J=5.1 Hz), 3.19 (4H, t, J=5.1Hz), 1.49 (9H, s)

[0677] ESIMS(m/z): 453(M+H)⁺

Example 66Ethyl[6-(4-t-Butoxycarbonylpiperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetate

[0678] Dry THF (2 ml) was added in an argon atmosphere to the compound(100 mg) obtained in Example 49. The mixture was cooled to −78° C. A 1.0M THF solution (347 μl) of bis(trimethylsilyl)amide sodium was slowlyadded thereto. The temperature of the mixture was raised to −50° C., andthe mixture was stirred for30 min. The reaction solution was cooled to−78° C. Ethyl bromoacetate (79 mg) was slowly added thereto. Thetemperature of the mixture was raised to room temperature, and themixture was then stirred overnight. A saturated aqueous ammoniumchloride solution (5 ml) was then added thereto, followed by separationwith ethyl acetate and water. The ethyl acetate layer was washed with anaqueous sodium chloride solution, dried over magnesium sulfate, and thenconcentrated under the reduced pressure. The residue was purified bychromatography on silica gel (ethyl acetate:hexane=1:2) to give 119 mgofethyl[6-(4-t-butoxycarbonylpiperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]acetate.

[0679]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.11 (1H, dd, J=2.5, 8.3 Hz), 4.44 (2H, s), 4.38 (2H, s), 4.21 (2H, q,J=6.9 Hz), 3.58 (4H, t, J=5.0 Hz), 3.17 (4H, t, J=5.0 Hz), 1.49 (9H, s),1.24 (3H, t, J=6.9 Hz)

[0680] TSIMS(m/z): 404(M+H)⁺

Example 67Ethyl{6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-1-oxo-1,3-dihydro-isoindol-2-yl}acetate

[0681] In the same manner as in Example 52, the title compound wasprepared from the compound obtained in Example 66.

[0682]¹H-NMR(CDCl₃) δ:7.35 (1H, d, J=2.5 Hz), 7.32 (1H, d, J=8.3 Hz),7.29-7.16 (10H, m), 7.11 (1H, dd, J=2.5, 8.3 Hz), 4.44 (2H, s), 4.38(2H, s), 4.21 (2H, q, J=6.9 Hz), 4.02 (1H, t, J=7.7 Hz), 3.25 (4H, t,J=4.8 Hz), 2.57 (4H, t, J=4.8 Hz), 2.32 (4H, brs), 1.24 (3H, t, J=6.9Hz)

[0683] TSIMS(m/z): 498(M+H)⁺

Example 68 2-Cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0684] (a) cyclohexylamine (5.2 ml) was added to a solution ofhomophthalic acid (4.86 g) in toluene (100 ml). The mixture was heatedunder reflux at 110° C. for 6.5 hr. The precipitated crystals werecollected by filtration. The filtrate was concentrated under the reducedpressure. The residue was purified by chromatography on silica gel(hexane:ethyl acetate=1:1) to give the title compound (110 mg).Separately, a portion (1.0 g) of the crystals collected by thefiltration was stirred with heating at 160° C. for 4 hr. Water was addedto the reaction product. The mixture was extracted with ethyl acetate.The extract was dried over anhydrous magnesium sulfate. The solvent wasthen removed by distillation. The residue was purified by chromatographyon silica gel (hexane:ethyl acetate=1:1) to giveN-cyclohexylhomophthalimide (424 mg).

[0685]¹H-NMR(CDCl₃) δ:1.35 (2H, m), 1.68 (6H, m), 2.39 (2H, m), 4.00(2H, s), 4.79 (1H, m), 7.23 (1H, d, J=7.5), 7.42 (1H, t, J=7.5), 7.55(1H, t, J=7.5), 8.11 (1H, d, J=7.5)

[0686] EIMS(m/z): 243(M⁺)

[0687] (b) Sodium boron hydride (393 mg) was added to a solution of thecompound (420 mg), obtained in step (a) just above, dissolved in a mixedsolution (10 ml) of methylene chloride:methanol=1:1 under cooling in anice bath. The mixture was stirred at room temperature for 4 hr. Thereaction solution was concentrated to dryness. Water was added to theresidue. The mixture was extracted with methylene chloride, and thendried over anhydrous magnesium sulfate. The solvent was then removed bydistillation. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain2-cyclohexyl-3-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (185 mg).

[0688]¹H-NMR(CDCl₃) δ:1.50 (10H, m), 2.62 (1H, bs), 3.10 (2H, m), 4.56(1H, m), 5.32 (1H, bs), 7.21 (1H, d, J=7.4), 7.35 (1H, t, J=7.6), 7.44(1H, dt, J=1.5, 7.4), 8.05 (1H, d, J=1.5, 7.6)

[0689] FABMS(m/z): 246(M+H)⁺

[0690] (c) The compound (22 mg) obtained in step (b) just above wasstirred in a mixed solution of ethanol:concentrated hydrochloricacid=10:1 at room temperature for 30 min. Water was added to thereaction solution. The mixture was extracted with ethyl acetate, andthen dried over anhydrous magnesium sulfate. The solvent was thenremoved by distillation. The residue was purified by chromatography onsilica gel (hexane:ethyl acetate=1:1) to give2-cyclohexyl-2H-isoquinolin-1-one (18 mg).

[0691]¹H-NMR (CDCl₃) δ:1.54 (10H, m), 5.01 (1H, m), 6.50 (1H, d, J=7.6),7.17 (1H, d, J=7.6), 7.47 (2H, m), 7.62 (1H, dt, J=1.4, 8.0), 8.45 (1H,d, J=8.0)

[0692] TSIMS(m/z): 228(M+H)⁺

[0693] (d) The compound (200 mg) obtained in step (c) just above wasdissolved in a mixed solution (10.7 ml) of ethanol : concentratedhydrochloric acid=15:1. 10% Pd-C (60 mg) was added to the solution,followed by hydrogenation for 3.5 hr. Pd-C was removed by filtrationthrough Celite. The filtrate was concentrated under the reducedpressure. Water was then added the residue. The mixture was extractedwith ethyl acetate. The organic layer was then dried over anhydrousmagnesium sulfate. The solvent was then removed by distillation to give2-cyclohexyl-3,4-dihydro-2H-isoquinolin-1-one (168 mg).

[0694]¹H-NMR(CDCl₃) δ:1.44 (4H, m), 1.79 (6H, m), 2.90 (2H, t, J=6.6),3.44 (2H, t, J=6.6), 4.65 (1H, m), 7.15 (1H, d, J=7.4), 7.31 (1H, t,J=7.4), 7.38 (1H, t, J=7.6), 8.08 (1H, d, J=7.6)

[0695] TSIMS(m/z): 230(M+H)⁺

[0696] (e) In the same manner as in step (c) of Example1,2-cyclohexyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (142 mg) wasprepared from the compound (156 mg) obtained in step (d) just above.

[0697]¹H-NMR(CDCl₃) δ:1.45 (4H, m), 1.79 (6H, m), 3.01 (2H, t, J=6.4),3.51 (2H, t, J=6.4), 4.63 (1H, m), 7.35 (1H, d, J=8.2), 8.21 (1H, dd,J=2.4, 8.2), 8.87 (1H, d, J=2.4)

[0698] TSIMS(m/z): 275(M+H)⁺

[0699] (f) In the same manner as in step (d) of Example1,7-amino-2-cyclohexyl-3,4-dihydro-2H-isoquinolin-1-one (117 mg) wasprepared from the compound (142 mg) obtained in step (e) just above.

[0700]¹H-NMR(CDCl₃) δ:1.42 (4H, m), 1.71 (6H, m), 2.78 (2H, t, J=6.5),3.39 (2H, t, J=6.5), 3.73 (2H, bs), 4.64 (1H, m), 6.72 (1H, dd, J=2.4,7.9), 6.94 (1H, d, J=7.9), 7.40 (1H, d, J=2.4)

[0701] TSIMS(m/z): 245(M+H)⁺

[0702] (g) In the same manner as in step (e) of Example 1,2-cyclohexyl-7-(piperazin-1-yl)-3,4-dihydro-2H- isoquinolin-1-one (310mg) was prepared from the compound (440 mg) obtained in step (f) justabove.

[0703]¹H-NMR(CDCl₃) δ:1.26 (4H, m), 1.73 (6H, m), 2.83 (2H, t, J=6.4),3.09 (4H, t, J=2.2), 3.21 (4H, t, J=2.2), 3.42 (2H, t, J=6.4), 4.66 (1H,m), 6.98 (1H, dd, J=2.4, 8.4), 7.07 (1H, d, J=8.4), 7.65 (1H, d, J=2.4)

[0704] TSIMS(m/z): 314(M+H)⁺

[0705] (h) In the same manner as in step (f) of Example 1, the titlecompound (12 mg) was prepared from the compound (24 mg) obtained in step(g) just above and 3,3-diphenylpropyl bromide.

[0706]¹H-NMR(CDCl₃) δ:1.45 (10H, m), 2.33 (bs, 4H), 2.57 (4H, t, J=4.6),2.82 (2H, t, J=6.5), 3.23 (4H, t, J=4.6), 3.42 (2H, t, J=6.5), 4.02 (1H,t, J=7.0), 4.67 (1H, m), 6.98 (1H, dd, J=2.6, 8.3), 7.05 (1H, d, J=8.3),7.22 (10H, m), 7.65 (1H, d, J=2.6)

[0707] TSIMS(m/z): 508(M+H)⁺

Example 692-Cyclohexyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0708] Di-t-butyl dicarbonate (176 mg) and triethylamine (0.12 ml) wereadded to a solution of the compound (125 mg), obtained in step (g) ofExample 68, in tetrahydrofuran (10 ml) . The mixture was stirred at roomtemperature for one hr. Water was added to the reaction solution. Themixture was extracted with ethyl acetate. The organic layer was thendried over anhydrous magnesium sulfate. The solvent was then removed bydistillation. The residue was purified by chromatography on silica gel(hexane ethyl acetate=9:1) to give the title compound (157 mg).

[0709]¹H-NMR(CDCl₃) δ:1.43 (4H, m), 1.49 (9H, s), 1.73 (6H, m), 2.83(2H, t, J=6.5), 3.15 (4H, t, J=5.2), 3.42 (2H, t, J=6.5), 3.58 (4H, t,J=5.2), 4.65 (1H, m), 6.98 (1H, dd, J=2.5, 8.2), 7.07 (1H, d, J=8.2),7.65 (1H, d, J=2.5)

[0710] TSIMS(m/z): 414(M+H)⁺

Example 702-Cyclohexyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-2H-isoquinolin-1-one

[0711] 10% Pd-C (150 mg) was added to a solution of the compound (146mg), obtained in Example 69, in ethanol (5 ml). The mixture was heatedat 75° C. for 4 hr. The Pd-C was removed by filtration through Celite.The filtrate was then concentrated under the reduced pressure to givethe title compound (122 mg).

[0712]¹H-NMR(CDCl₃) δ:1.27 (4H, m), 1.49 (9H, s), 1.92 (6H, m), 3.25(4H, t, J=5.1), 3.61 (4H, t, J=5.1), 5.00 (1H, m), 6.46 (1H, d, J=7.5),7.03 (1H, d, J=7.5), 7.31 (1H, dd, J=2.7, 8.7), 7.42 (1H, d, J=9.7),7.85 (1H, d, J=2.7)

[0713] TSIMS(m/z): 412(M+H)⁺

Example 712-Cyclohexyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2H-isoquinolin-1-one

[0714] Trifluoroacetic acid (1 ml) was added under cooling in an icebath to the compound (10 mg) obtained in Example 70. The mixture wasstirred for 2 hr. A saturated aqueous sodium hydrogencarbonate solutionwas then added to the reaction solution. The mixture was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate. The solvent was then removed by distillation.N,N-dimethylformamide (2 ml) was added to the residue to prepare asolution. Potassium carbonate (10 mg) and 3,3-diphenylpropyl bromide (4mg) were then added to the solution. The mixture was stirred at roomtemperature overnight. Water was added to the reaction solution. Themixture was then extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was then removed bydistillation. The residue was purified by preparative TLC (hexane:ethylacetate=1:1) to give the title compound (10 mg).

[0715]¹H-NMR(CDCl₃) δ:1.91 (10H, m), 2.34 (4H, m), 2.60 (4H, t, J=5.0),3.32 (4H, t, J=5.0), 4.02 (1H, t, J=7.0), 5.00 (1H, m), 6.46 (1H, d,J=7.4), 7.02 (1H, d, J=7.4), 7.27 (1H, m), 7.41 (1H, d, J=8.9), 7.84(1H, d, J=2.2)

[0716] TSIMS(m/z): 506(M+H)⁺

Example 722-Benzyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0717] In the same manner as in Example 66, the title compound (80 mg)was obtained from 7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-1H-isoquinolin-1-one (100 mg), synthesizedaccording to the method described in J. Med. Chem., 39, 4583 (1996), andbenzyl bromide (0.053 ml).

[0718]¹H-NMR(CDCl₃) δ:1.49 (9H, s), 2.86 (2H, t, J=6.7), 3.18 (4H, t,J=5.0), 3.47 (2H, t, J=6.7), 3.59 (4H, t, J=5.0), 4.80 (1H, s), 7.01(1H, dd, J=2.2, 8.3), 7.08 (1H, d, J=8.3), 7.32 (5H, m), 7.72 (1H, d,J=2.2)

[0719] ESIMS(m/z): 422(M+H)⁺

Example 732-Benzyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0720] The title compound (43 mg) was obtained in the same manner as inExample 71, except that the compound (60 mg) obtained in Example 72 wasused as the starting compound and hydrochloric acid was used instead oftrifluoroacetic acid.

[0721]¹H-NMR(CDCl₃) δ:2.32 (4H, m), 2.57 (4H, t, J=4.9), 2.84 (2H, t,J=6.5), 3.24 (4H, t, J=4.9), 3.45 (2H, t, J=6.5), 4.10 (1H, t, J=7.1),6.99 (1H, dd, J=2.5, 8.5), 7.05 (1H, d, J=8.5), 7.30 (14H, m), 7.71 (1H,d, J=2.5)

[0722] TSIMS(m/z): 516(M+H)⁺

Example 742-Methyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0723] The title compound was obtained in the same manner as in Example66, except that methyl iodide was used instead of ethyl bromoacetate.

[0724]¹H-NMR(CDCl₃) δ:1.47 (9H, s), 2.90 (2H, t, J=6.6), 3.13 (m, 7H),3.54 (6H, m), 6.96 (1H, dd, J=1.2, 8.3), 7.07 (1H, d, J=8.3), 7.64 (1H,d, J=1.2)

[0725] TSIMS(m/z): 346(M+H)⁺

Example 757-[4-(3,3-Diphenyl-1-propyl)-piperazin-1-yl)-3,4-dihydro-2-methyl-2H-isoquinolin-1-one

[0726] In the same manner as in Example 71, the title compound wasobtained from the compound obtained in Example 74.

[0727]¹H-NMR(CDCl₃) δ:2.44 (4H, m), 2.93 (2H, t, J=6.5), 3.16 (7H, m),3.54 (4H, m), 4.06 (1H, m), 4.11 (2H, t, J=6.5), 6.99 (11H, dd, J=2.6,8.2), 7.09 (1H, d, J=8.2), 7.26 (10H, m), 7.65 (1H, d, J=2.6)

[0728] FABMS(m/z): 440(M+H)⁺

Example 762-Cyclohexylmethyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0729] The title compound was obtained in the same manner as in Example66, except that cyclohexylmethyl bromide was used instead of ethylbromoacetate.

[0730]¹H-NMR(CDCl₃) δ:1.23 (5H, m), 1.48 (9H, s), 1.72 (6H, m), 2.89(2H, t, J=6.5), 3.15 (4H, t, J=5.0), 3.40 (2H, d, J=7.1), 3.52 (2H, t,J=6.5), 3.57 (4H, t, J=5.0), 6.99 (1H, dd, J=2.7, 8.2), 7.08 (1H, d,J=8.2), 7.65 (1H, d, J=2.7)

[0731] TSIMS(m/z): 428(M+H)⁺

Example 772-Cyclohexylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0732] In the same manner as in Example 71, the title compound wasobtained from the compound obtained in Example 76.

[0733]¹H-NMR(CDCl₃)δ:1.72 (5H, m), 2.34 (4H, m), 2.58 (4H, t, J=4.4),2.89 (2H, t, J=6.6), 3.22 (4H, t, J=4.4), 3.40 (2H, d, J=6.9), 3.51 (2H,t, J=6.6), 4.00 (1H, t, J=7.0), 6.97 (1H, dd, J=2.5, 8.3), 7.06 (1H, d,J=8.3), 7.20 (10H, m), 7.63 (1H, d, J=2.5)

[0734] TSIMS(m/z): 522(M+H)⁺

Example 782-Cyclopropylmethyl-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0735] The title compound was obtained in the same manner as in Example66, except that cyclopropylmethyl bromide was used instead of ethylbromoacetate.

[0736]¹H-NMR(CDCl₃) δ:0.31 (2H, m), 0.53 (2H, m), 1.04 (1H, m), 1.47(9H, s), 2.92 (2H, t, J=6.5), 3.15 (4H, t, J=5.1), 3.47 (2H, d, J=6.5),3.57 (4H, t, J=5.1), 3.62 (2H, t, J=6.5), 6.99 (1H, dd, J=2.7, 8.2),7.09 (1H, d, J=8.2), 7.65 (1H, d, J=2.7)

[0737] TSIMS(m/z): 386(M+H)⁺

Example 792-Cyclopropylmethyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0738] In the same manner as in Example 71, the title compound wasprepared from the compound obtained in Example 78.

[0739]¹H-NMR(CDCl₃) δ:0.30 (2H, m), 0.52 (2H, m), 1.04 (1H, m), 2.30(4H, m), 2.57 (4H, t, J=4.9), 2.91 (2H, t, J=6.6), 3.23 (4H, t, J=4.9),3.47 (2H, d, J=6.9), 3.62 (2H, t, J=6.6), 4.01 (1H, t, J=7.1), 6.98 (1H,dd, J=2.6, 8.3), 7.07 (1H, d, J=8.3), 7.20 (10H, m), 7.65 (1H, d, J=2.6)

[0740] TSIMS(m/z): 480(M+H)⁺

Example 802-(4-Chlorobenzyl)-7-(4-t-butoxycarbonyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one

[0741] The title compound was obtained in the same manner as in Example66, except that 4-chlorobenzyl chloride was used instead of ethylbromoacetate.

[0742]¹H-NMR(CDCl₃) δ:1.49 (9H, s), 2.86 (2H, t, J=6.6), 3.17 (4H, t,J=5.0), 3.45 (2H, t, J=6.6), 3.58 (4H, t, J=5.0), 4.74 (2H, s), 7.00(1H, dd, J=2.6, 8.3), 7.08 (1H, d, J=8.3), 7.28 (4H, m), 7.69 (1H, d,J=2.6)

[0743] TSIMS(m/z): 456(M+H)⁺

Example 812-(4-Chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0744] In the same manner as in Example 71, the title compound wasprepared from the compound obtained in Example 80.

[0745]¹H-NMR(CDCl₃) δ:2.33 (4H, m), 2.58 (4H, t, J=4.8), 2.85 (2H, t,J=6.6), 3.25 (4H, t, J=4.8), 3.45 (2H, t, J=6.6), 4.03 (1H, t, J=7.1),4.75 (2H, s), 7.00 (1H, dd, J=2.5, 8.3), 7.06 (1H, d, J=8.3), 7.30 (14H,m), 7.70(1H, d, J=2.5)

[0746] TSIMS(m/z): 550(M+H)⁺

Example 827-[4-(3,3-Diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0747] In the same manner as in step (f) of Example 1, the titlecompound was obtained from 7-(piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one, synthesized according to the methoddescribed in J. Med. Chem., 39, 4583 (1996), and 3,3-diphenylpropylbromide.

[0748]¹H-NMR(CDCl₃) δ:2.32 (4H, m), 2.57 (4H, t, J=5.0), 2.91 (2H, t,J=6.4), 3.24 (4H, t, J=5.0), 3.53 (2H, dt, J=2.9, 6.4), 4.02 (1H, t,J=7.0), 5.96 (1H, bs), 7.02 (1H, dd, J=2.7, 8.4), 7.11 (1H, d, J=8.4),7.61 (1H, d, J=2.7)

[0749] FABMS(m/z): 426(M+H)⁺

Example 832-(2-Chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0750] In the same manner as in Example 66, the title compound wasprepared from the compound obtained in Example 82 and 2-chlorobenzylchloride.

[0751]¹H-NMR(CDCl₃) δ:2.35 (4H, m), 2.60 (4H, t, J=4.8), 2.90 (2H, t,J=6.6), 3.26 (4H, t, J=4.8), 3.53 (2H, t, J=6.6), 4.02 (1H, t, J=7.1),4.92 (2H, s), 7.01 (1H, dd, J=2.5, 8.3), 7.08 (1H, d, J=8.3), 7.26 (14H,m), 7.70 (1H, d, J=2.5)

[0752] TSIMS(m/z): 550(M+H)⁺

Example 842-(3-Chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0753] In the same manner as in Example 66, the title compound wasprepared from the compound obtained in Example 82 and 3-chlorobenzylchloride.

[0754]¹H-NMR(CDCl₃) δ:2.34 (4H, m), 2.59 (4H, t, J=4.6), 2.87 (2H, t,J=6.0), 3.25 (4H, t, J=4.6), 3.47 (2H, t, J=6.0), 4.02 (1H, t, J=7.2),4.76 (2H, s), 7.00 (1H, dd, J=2.6, 8.3), 7.08 (1H, d, J=8.3), 7.28 (14H,m), 7.71 (1H, d, J=2.6)

[0755] TSIMS(m/z): 550(M+H)⁺

Example 852,3-Dihydro-3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1H-isoindol-1-one

[0756] 2,3-Dihydro-3,3-dimethyl-1H-isoindol-1-one was synthesizedaccording to the method described in Angew. chem. Int. Ed. Engl., 7, 373(1968). In the same manner as in step (e) and later steps of Example 68,the title compound was obtained from this compound.

[0757]¹H-NMR(CDCl₃) δ:1.51 (6H, s), 2.25-2.38 (4H, m), 2.58 (4H, m),3.25 (4H, m), 4.01 (1H, t, J=7.5), 6.15 (1H, s), 7.10-7.39 (13H)

[0758] EIMS(m/z): 411(M)⁺

Example 863-Cyclohexyl-3,4-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2H-1,3-benzoxazin-4-one

[0759] (a) Thionyl chloride (20 ml) was added to 5-nitrosalicylic acid(5 g). The mixture was heated under reflux for 2 hr. Thionyl chloridewas removed by distillation under the reduced pressure. Toluene wasadded to the residue, and the mixture was concentrated. This procedurewas repeated twice. The residue was dissolved in methylene chloride (40ml). Cyclohexylamine (9.4 ml) was added under ice cooling to thesolution. The mixture was stirred at room temperature overnight. Thereaction solution was diluted with ethyl acetate. The diluted solutionwas washed with water, dilute hydrochloric acid, and water in thatorder, and then dried over magnesium sulfate. The solvent was thenremoved by distillation under the reduced pressure to give 6.9 g ofN-cyclohexyl-5-nitrosalicylamide.

[0760]¹H-NMR(CDCl₃) δ:1.19-1.50 (5H, m), 1.71 (1H, m), 1.83 (2H, m),2.06 (2H, m), 3.99 (1H, m), 6.39 (1H, brd, J=6.1), 7.06 (1H, d, J=9.2),8.27 (1H, dd, J=2.5, 9.2), 8.38 (1H, d, J=2.5), 13.52 (1H, br.s)

[0761] TSIMS(m/z): 263(M−H)⁻

[0762] (b) Formic acid (5 ml) and 37% formaldehyde (5 ml) were added tothe compound (1 g) obtained in step (a) just above. The mixture washeated under reflux for 5 hr. The reaction solution was cooled. About 20ml of water was added thereto. The precipitated crystals were collectedby filtration, and then dried to give 981 mg of3-cyclohexyl-3,4-dihydro-6-nitro-2H-benzoxazin-4-one.

[0763]¹H-NMR(CDCl₃) δ:1.15 (1H, m), 1.35-1.52 (4H, m), 1.73 (1H, brd),1.87 (4H, brd), 4.48 (1H, m), 5.26 (2H, s), 7.09 (1H, d, J=9.0), 8.31(1H, dd, J=2.7, 9.0), 8.87 (1H, d, J=2.7)

[0764] TSIMS(m/z): 276(M)⁺

[0765] (c) In the same manner as in step (f) and later steps of Example68, the title compound was obtained from the compound obtained in step(b) just above.

[0766]¹H-NMR(CDCl₃) δ:1.14 (1H, m), 1.34-1.49 (4H, m), 1.70 (1H, brd),1.83 (4H, brd), 2.22-2.37 (4H, m), 2.57 (4H, m), 3.15 (4H, m), 4.01 (1H,t, J=7.3), 4.46 (1H, m), 5.09 (2H, s), 6.86 (1H, d, J=8.8), 7.04 (1H,dd, J=2.9, 8.8), 7.15-7.30 (10H), 7.47 (1H, d, J=2.9)

[0767] TSIMS(m/z): 510(M+H)⁺

Example 873-Cyclohexyl-3,4-dihydro-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2H-1,3-benzothiazin-4-one

[0768] (a) Isobutyl chloroformate (1.43 ml) was added under ice coolingto a solution of 2-chloro-5-nitrobenzoic acid (2.01 g) and triethylamine(1.53 ml) in methylene chloride (40 ml). The mixture was stirred underice cooling for 45 min. Thereafter, cyclohexylamine (1.25 ml) was addedthereto. The reaction solution was stirred at room temperature for 1.5hr. The precipitated crystals were dissolved in chloroform. The organiclayer was washed with water, dilute hydrochloric acid, and water in thatorder, dried over magnesium sulfate, and then concentrated under thereduced pressure. Ethyl ether was added to the residue. The precipitatedcrystals were collected by filtration, and then dried to give 2.63 g ofN-cyclohexyl-2-chloro-5-nitrobenzamide.

[0769]¹H-NMR(CDCl₃) δ:1.18-1.81 (8H), 2.07 (2H, m), 4.03 (1H, m), 5.99(1H, br.s), 7.58 (1H, d, J=8.7), 8.20 (1H, dd, J=2.7, 8.7), 8.47 (1H, d,J=2.7)

[0770] (b) A solution of potassium hydrosulfide obtained by passinghydrogen sulfide into an aqueous solution (10 ml) of potassium hydroxide(1.68 g) was added to an ethanol solution (20 ml) of the compound (850mg) synthesized in step (a) just above. The mixture was stirred at 90°C. for 2 hr. Argon gas was bubbled into the mixture. The solvent wasthen removed by distillation. Water was added to the residue. Themixture was acidified by the addition of 5 N hydrochloric acid. Theprecipitated crystals were collected by filtration. Formic acid (6 ml)and 37% formaldehyde (6 ml) were added to the crystals, followed byheating under reflux for 3 hr. The reaction solution was cooled. Waterwas added thereto, and the resultant precipitate was collected byfiltration. The precipitate collected by filtration was separated withchloroform and water. The insolubles were removed by filtration. Thechloroform layer was concentrated. The residue was subjected to columnchromatography on silica gel. In this case, elution was carried outusing chloroform. Thus, 195 mg of 3-cyclohexyl-3,4-dihydro-6-nitro-2H-benzothiazin-4-one was obtained.

[0771]¹H-NMR(CDCl₃) δ:1.15 (1H, m), 1.39-1.51 (4H, m), 1.73 (1H, br.d),1.82-1.92 (4H, m), 4.58 (2H, s), 4.61 (1H, m), 7.44 (1H, d, J=8.5), 8.18(1H, dd, J=2.4, 8.5), 8.97 (1H, d, J=2.4)

[0772] TSIMS(m/z): 292(M)⁻

[0773] (c) In the same manner as in step (f) and later steps of Example68, the title compound was obtained from the compound obtained in step(b) just above.

[0774]¹H-NMR(CDCl₃) δ:1.13 (1H, m), 1.37-1.51 (4H, m), 1.70 (1H, br.d),1.81-1.89 (4H, m), 2.24-2.37 (4H, m), 2.55 (4H), 3.21 (4H), 4.01 (1H, t,J=7.1), 4.45 (2H, s), 4.61 (1H, m), 6.93 (1H, dd, J=2.8, 8.7), 7.13 (1H,d, J=8.7), 7.15-7.31 (10H) , 7.66 (1H, d, J=2.8)

[0775] TSIMS(m/z): 526(M+H)⁺

Example 882-Cyclohexyl-6-(4-(2-diphenylaminoethyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0776] (a) In the same manner as described in Heterocycles, Vol. 19,No.1, 75-82 (1982), (2,2-diethoxyethyl)-diphenylamine was obtained fromdiphenylamine and bromoacetaldehyde diethyl acetal.

[0777]¹H-NMR(CDCl₃) δ:1.18 (6H, t, J=12.7 Hz), 3.50 (2H, q, J=12.7 Hz),3.65 (2H, q, J=12.7 Hz), 3.88 (2H, d, J=5.3 Hz), 4.70 (1H, t, J=5.3 Hz),6.93 (2H, t, J=7.3 Hz), 7.08 (4H, m), 7.24 (4H, m)

[0778] TSIMS(m/z): 286(M+H)⁺

[0779] (b) The compound (700 mg) obtained in step (a) just above wasstirred at room temperature overnight in a solvent (40 ml) ofacetone:water=7:1 in the presence of Amberlyst 15 (50 mg). The reactionsolution was filtered through a filter paper. The filtrate was subjectedto distillation under the reduced pressure, and purification was thencarried out by column chromatography on silica gel (eluent hexane:ethylacetate=10:1) to give N,N-diphenylaminoacetaldehyde (250 mg).

[0780]¹H-NMR(CDCl₃) δ:4.36 (2H, d, J=2.5 Hz), 6.92 (5H, m), 7.25 (5H,m), 9.78 (1H, t, J=2.5 Hz)

[0781] TSIMS(m/z): 212(M+H)⁺

[0782] (c) In the same manner as in Example 38, the title compound (50mg) was obtained from the compound (50 mg) obtained in step (b) justabove and the compound (70 mg) obtained in step (e) of Example 1.

[0783]¹H-NMR(CDCl₃) δ:1.39-1.84 (10H, m), 2.65 (4H, t, J=5.0 Hz), 2.72(2H, t, J=7.5 Hz), 3.23 (4H, t, J=5.0 Hz), 3.91 (2H, t, J=7.5 Hz), 4.22(1H, br), 4.25 (2H, s), 6.94 (2H, dt, J=0.9, 7.5 Hz), 7.02 (4H, dd,J=0.7, 7.8 Hz), 7.08 (1H, dd, J=2.5, 8.3 Hz), 7.28 (4H, dt, J=0.7, 7.8Hz), 7.31 (1H, s), 7.35 (1H, d, J=2.4 Hz)

[0784] TSIMS(m/z): 495(M+H)⁺

Example 894-(2-cyclohexyl-1-oxo-2,3-dihydro-1H-isoindol-6-yl)piperazine-1-carboxylicacid benzhydrylamide

[0785] (a) Benzhydrylamine (1.83 g) was dissolved in dichloromethane(3.0 ml). Carbonyldiimidazole (1.78 g) was added to the solution. Themixture was stirred at room temperature overnight. Water anddichloromethane were added thereto. The mixture was stirred, and thenextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate. The solvent was then removed bydistillation is to give imidazole-1-carboxylic acid benzhydrylamide.

[0786]¹H-NMR(CDCl₃) δ:6.29 (1H, d, J=7.7 Hz), 6.92 (1H, bs), 7.34 (12H,m), 7.96 (1H, bs)

[0787] TSIMS(M/Z): 278(M+H)⁺

[0788] (b) The compound (138 mg) obtained in step (a) just above wasdissolved in toluene (5 ml). The compound (149 mg) obtained in Example1e and triethylamine (8.3 ml) were added to the solution. The mixturewas stirred at room temperature for 1.5 hr. The reaction solution wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate. The solvent was then removed by distillation. Theresidue was developed in preparative TLC (chloroform:methanol=9:1) togive the title compound (127 mg).

[0789]¹H-NMR(CDCl₃) δ:1.62 (10H, m), 3.24 (4H, m), 3.60 (4H, m), 4.28(3H, bs), 5.06 (1H, d, J=7.1 Hz), 6.17 (1H, d, J=7.1 Hz), 7.10 (1H, dd,J=2.5, 8.2 Hz), 7.30 (12H, m)

[0790] TSIMS(M/Z): 509(M+H)⁺

Example 90 2-Benzyl-7-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0791] The compound (121 mg) obtained in Example 72 was dissolved inethyl acetate (3.0 ml) and concentrated hydrochloric acid (0.7 ml). Thesolution was stirred at room temperature for 2 hr. The reaction solutionwas neutralized with a saturated aqueous sodium hydrogencarbonatesolution, and then extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was then removed bydistillation. In the same manner as in Example 38, the title compound(48 mg) was obtained from the residue and 4,4-diphenylbutylaldehyde.

[0792]¹H-NMR(CDCl₃) δ:1.54 (2H, m), 2.12 (2H, m), 2.45 (2H, t, J=7.5Hz), 2.57 (4H, m), 2.84 (2H, t, J=6.6 Hz), 3.24 (4H, m), 3.45 (2H, t,J=6.6 Hz), 3.94 (1H, t, J=7.8 Hzm), 4.81 (2H, s), 7.00 (1H, dd, J=2.6,8.3 Hz), 7.06 (1H, d, J=8.3 Hz), 7.28 (10H, m), 7.73 (1H, d, J=2.6 Hz)

[0793] TSIMS(M/Z): 530(M+H)⁺

Example 917-[4-(Benzhydryloxycarbonyl)piperazin-1-yl]-2-benzyl-3,4-dihydro-2H-isoquinolin-1-one

[0794] The compound (100 mg) obtained in Example 72 was dissolved inethyl acetate (2.5 ml) and concentrated hydrochloric acid (0.5 ml). Thesolution was stirred at room temperature for 2 hr. The reaction solutionwas neutralized with a saturated aqueous sodium hydrogencarbonatesolution, and then extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was then removed bydistillation. In the same manner as in Example 28, the title compound(104 mg) was obtained from the residue and benzhydryloxycarbonyl azide.

[0795]¹H-NMR(CDCl₃) δ:2.86 (2H, t, J=6.6 Hz), 3.18 (4H, m), 3.47 (2H, t,J=6.6 Hz), 3.76 (4H, m), 4.80 (2H, s), 6.85 (1H, s), 7.00 (1H, dd,J=2.6, 8.3 Hz), 7.08 (1H, d, J=8.3 Hz), 7.35 (15H, m), 7.73 (1H, d,J=2.6 Hz)

[0796] TSIMS(M/Z): 532(M+H)⁺

Example 922-Benzyl-7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0797] (a) 7-Piperazin-1-yl-3,4-dihydro-2H-isoquinolin 1-one (100 mg)synthesized according to the method described in J. Med. Chem., 39, 4583(1996) was dissolved in N, N-dimethylformamide (5 ml). Potassiumcarbonate (71 mg) and 4-chloro benzyl bromide (106 mg) were added to thesolution. The mixture was stirred at room temperature for 2 hr. Waterwas added to the reaction solution. The mixture was then extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate. The solvent was then removed by distillation under the reducedpressure. The residue was purified by column chromatography on silicagel (chloroform:methanol=9:1) to give7-[4-(4-chlorobenzyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one(75 mg).

[0798]¹H-NMR(CDCl₃) δ:2.59 (4H, m), 2.90 (2H, t, J=5.4 Hz), 3.23 (4H,m), 3.52 (4H, m), 6.40 (1H, bs), 7.00 (1H, dd, J=2.6, 8.3 Hz), 7.10 (1H,d, J=8.3 Hz), 7.29 (4H, m), 7.62 (1H, d, J=2.6 Hz)

[0799] FABMS(M/Z): 356(M+H)⁺

[0800] (b) In the same manner as in Example 51, the title compound (45mg) was obtained from the compound (70 mg) obtained in step (a) justabove and benzyl bromide (32 mg).

[0801]¹H-NMR(CDCl₃) δ:2.60 (4H, m), 2.85 (2H, t, J=6.6 Hz), 3.25 (4H,m), 3.46 (2H, t, J=6.6 Hz), 3.53 (2H, s), 4.79 (2H, s), 6.99 (1H, dd,J=2.5, 8.3 Hz), 7.06 (1H, d, J=8.3 Hz), 7.30 (9H, m), 7.72 (1H, d, J=2.5Hz)

[0802] ESIMS(M/Z): 446(M+H)⁺

Example 932-Cyclopropyl-6-[4-(4,4-diphenyl-1-butyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0803] In the same manner as in Example 38, the title compound (21 mg)was prepared from 2-cyclopropyl-(6-piperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one (66 mg) obtained in thecourse of the synthesis of the compound of Example 25 and4,4-diphenylbutylaldehyde (45 mg).

[0804]¹H-NMR(CDCl₃) δ:0.81-0.94 (4H, m), 1.46-1.56 (2H, m), 2.09 (2H,dt, J=7.7, 8.0 Hz), 2.40-2.50 (2H, m), 2.55 (4H, m), 2.91-2.97 (1H, m),3.22 (4H, m), 3.91 (1H, t, J=8.0 Hz), 4.22 (2H, s), 7.09 (1H, dd, J=2.4,8.3 Hz), 7.14-7.20 (2H, m), 7.23-7.31 (10H, m)

[0805] TSIMS(M/Z): 466(M+H)⁺

Example 942-Cyclopentyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0806] In the same manner as in Example 51, the title compound (44 mg)was prepared from the compound (50 mg) obtained in Example 50 andcyclopentyl bromide (27 mg).

[0807]¹H-NMR(CDCl₃) δ:1.56 (m, 8H), 2.33 (4H, m), 2.48 (4H, t, J=4.6Hz), 3.16 (4H, t, J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.20 (2H, s), 4.67(1H, m), 7.02-7.08 (12H, m), 7.26 (1H, d, J=2.5 Hz)

[0808] TSIMS(m/z): 480(M+H)⁺

Example 95 2-Cycloheptyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0809] In the same manner as in Example 51, the title compound (12 mg)was prepared from the compound (50 mg) obtained in Example 50 andcycloheptyl bromide (32 mg).

[0810]¹H-NMR(CDCl₃) δ:1.56 (12H, m), 2.33 (4H, m), 2.48 (4H, t, J=4.6Hz), 3.16 (4H, t, J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.20 (2H, s), 4.67(1H, m), 7.02-7.08 (12H, m), 7.26 (1H, d, J=2.5 Hz)

[0811] TSIMS(m/z): 508(M+H)⁺

Example 966-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-isopropyl-2,3-dihydro-1H-isoindol-1-one

[0812] In the same manner as in Example 51, the title compound (32 mg)was prepared from the compound (50 mg) obtained in Example 50 and2-bromopropane (148 mg).

[0813]¹H-NMR(CDCl₃) δ:1.27 (6H, d, J=6.8 Hz), 2.33 (4H, m), 2.48 (4H, t,J=4.6 Hz), 3.16 (4H, t, J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.25 (2H, s),4.66 (1H, qq, J=6.8, 6.8 Hz), 7.02-7.08 (12H, m), 7.26 (1H, d, J=2.5 Hz)

[0814] TSIMS(m/z): 454(M+H)⁺

Example 972-Allyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0815] In the same manner as in Example 51, the title compound (51 mg)was prepared from the compound (50 mg) obtained in Example 50 and allylbromide (22 mg).

[0816]¹H-NMR(CDCl₃) δ:2.21 (4H, m), 2.51 (4H, t, J=4.6 Hz), 3.18 (4H, t,J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.13 (2H, d, J=6.1 Hz), 4.16 (2H, s),5.10 (1H, s), 5.13 (1H, dd, J=1.3, 6.1 Hz), 5.76 (1H, m)

[0817] TSIMS(m/z): 452(M+H)⁺

Example 982-Cinnamyl-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0818] In the same manner as in Example 51, the title compound (28 mg)was prepared from the compound (50 mg) obtained in Example 50 andcinnamyl bromide (36 mg).

[0819]¹H-NMR(CDCl₃) δ:2.21 (4H, m), 2.51 (4H, t, J=4.6 Hz), 3.18 (4H, t,J=4.6 Hz), 3.39 (1H, d, J=1.3 Hz), 3.94 (1H, t, J=7.6Hz), 4.13 (1H, dd,J=1.3, 6.3 Hz), 4.22 (2H, s), 4.29 (2H, d, J=6.3 Hz), 6.13 (1H, m), 6.48(1H, d, J=15.8 Hz), 7.00-7.34 (16H, m)

[0820] TSIMS(m/z): 528(M+H)⁺

Example 996-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl)-2-(3-methoxybenzyl)-2,3-dihydro-1H-isoindol-1-one

[0821] In the same manner as in Example 51, the title compound (35 mg)was prepared from the compound (50 mg) obtained in Example 50 and3-methoxybenzyl chloride (17 mg).

[0822]¹H-NMR(CDCl₃) δ:2.33 (4H, m), 2.48 (4H, t, J=4.6 Hz), 3.16 (4H, t,J=4.6 Hz), 3.77 (3H, s), 4.02 (1H, t, J=7.6 Hz), 4.18 (2H, s), 4.76 (2H,s), 7.02-7.08 (16H, m), 7.38 (1H, d, J=2.5 Hz)

[0823] TSIMS(m/z): 532(M+H)⁺

Example 1006-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one

[0824] In the same manner as in Example 51, the title compound (48 mg)was prepared from the compound (50 mg) obtained in Example 50 anda-bromo-m-xylene (17 mg).

[0825]¹H-NMR(CDCl₃) δ:2.33 (7H, m), 2.48 (4H, t, J=4.6 Hz), 3.16 (4H, t,J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.16 (2H, s), 4.70 (2H, s), 7.00-7.08(16H, m), 7.26 (1H, d, J=2.5 Hz)

[0826] TSIMS(m/z): 516(M+H)⁺

Example 1016-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-2,3-dihydro-1H-isoindol-1-one

[0827] In the same manner as in Example 51, the title compound (52 mg)was prepared from the compound (50 mg) obtained in Example 50 and3-trifluoromethylbenzyl chloride (35 mg).

[0828]¹H-NMR(CDCl₃) δ:2.33 (4H, m), 2.48 (4H, t, J=4.6 Hz), 3.16 (4H, t,J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.17 (2H, s), 4.82 (2H, s), 7.00-7.08(16H, m), 7.26 (1H, d, J=2.5 Hz)

[0829] TSIMS(m/z): 570(M+H)⁺

Example 1026-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-nitrobenzyl)-2,3-dihydro-1H-isoindol-1-one

[0830] In the same manner as in Example 51, the title compound (38 mg)was prepared from the compound (50 mg) obtained in Example 50 and3-nitro benzyl bromide (39 mg).

[0831]¹H-NMR(CDCl₃) δ: 2.33 (4H, m), 2.48 (4H, t, J=4.6 Hz), 3.16 (4H,t, J=4.6 Hz), 3.94 (1H, t, J=7.6 Hz), 4.22 (2H, s), 4.87 (2H, s),6.98-7.08 (14H, m), 7.26 (1H, d, J=2.5 Hz), 8.12 (2H, d, J=6.9 Hz)

[0832] TSIMS(m/z): 547(M+H)⁺

Example 1036-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-2,3-dihydro-1H-isoindol-1-one

[0833] In the same manner as in Example 51, the title compound (40 mg)was prepared from the compound (50 mg) obtained in Example 50 and5-thiazolemethyl chloride (24 mg).

[0834]¹H-NMR(CDCl₃) δ:2.23 (4H, m), 2.48 (4H, t, J=4.6 Hz), 3.16 (4H, t,J=4.6 Hz), 3.94 (1H, t, J=7.6), 4.32 (2H, s), 4.87 (2H, s), 7.02 (1H,dd, J=8.3, 2.4 Hz), 7.08-7.23 (11H, m), 7.26 (1H, d, J=2.4 Hz),8.67-8.71 (2H, m)

[0835] TSIMS(m/z): 509(M+H)⁺

Example 1042-Benzyl-3,3-dimethyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one

[0836] The title compound (144 mg) was prepared from the compound (150mg) obtained in Example 85 and benzyl bromide.

[0837]¹H-NMR(CDCl₃) δ:1.32 (6H, s), 2.29-2.35 (4H, m), 2.58, (4H, br.t),3.26 (4H, br.t), 4.02 (1H, t, J=7.4 Hz), 4.73 (2H, s), 7.10-7.38, 15H)

[0838] TSIMS(M/Z): 530(M+H)⁺

Example 1053,3-Dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-2,3-dihydro-1H-isoindol-1-one

[0839] The title compound (154 mg) was prepared from the compound (150mg) obtained in Example 85 and 2-methyl benzyl bromide.

[0840]¹H-NMR (CDCl₃)δ:1.30 (6H, s), 2.29-2.36 (4H, m), 2.39 (3H, s),2.58 (4H, br.t), 3.26 (4H, br.t), 4.02 (1H, t, J=7.2 Hz), 4.74 (2H, s),7.10-7.38 (14H)

[0841] TSIMS(M/Z): 544(M+H)⁺

Example 1063,3-Dimethyl-6-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-2,3-dihydro-1H-isoindol-1-one

[0842] The title compound (48 mg) was prepared from the compound (150mg) obtained in Example 85 and 1-phenylethyl bromide.

[0843]¹H-NMR(CDCl₃) δ: 1.41 (3H, s), 1.48 (3H, s), 1.94 (3H, d, J=7.3Hz), 2.30-2.34 (4H, m), 2.57 (4H, br.t), 3.23 (4H, br.t), 4.01 (1H, t,J=7.3 Hz), 4.74 (1H, q, J=7.3 Hz), 7.08-7.52 (15H)

[0844] TSIMS(M/z): 544(M+H)⁺

Example 1072-Cyclobutyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0845] In the same manner as in Example 51, the title compound (21 mg)was prepared from the compound (100 mg) obtained in Example 82 andcyclobutyl bromide (47 mg).

[0846]¹H-NMR(CDCl₃) δ:1.70 (6H, m), 2.32 (4H, bs), 2.57 (4H, m), 2.89(2H, t, J=5.6 Hz), 3.22 (4H, m), 3.52 (2H, t, J=5.6 Hz), 4.02 (1H, m),5.20 (1H, m), 6.98 (1H, dd, J=3.0, 8.3 Hz), 7.06 (1H, d, J=8.3 Hz), 7.27(10H, m), 7.63 (1H, d, J=3.0 Hz)

[0847] TSIMS(M/Z): 480(M+H)⁺

Example 1082-Cyclopentyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0848] In the same manner as in Example 51, the title compound (71 mg)was prepared from the compound (100 mg) obtained in Example 82 andcyclopentyl bromide (52 mg).

[0849]¹H-NMR(CDCl₃) δ:1.73 (8H, m), 2.32 (4H, bs), 2.57 (4H, m), 2.84(2H, t, J=6.4 Hz), 3.23 (4H, m), 3.40 (2H, t, J=6.4 Hz), 4.02 (1H, t,J=7.0 Hz), 5.20 (1H, m), 6.97 (1H, dd, J=2.6, 8.3 Hz), 7.05 (1H, d,J=8.3 Hz), 7.27 (10H, m), 7.65 (1H, d, J=2.6 Hz)

[0850] TSIMS(M/Z): 494(M+H)⁺

Example 1092-Cycloheptyl-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0851] In the same manner as in Example 51, the title compound (26 mg)was prepared from the compound (50 mg) obtained in Example 82 andcycloheptyl bromide (30 mg).

[0852]¹H-NMR(CDCl₃) δ:1.67 (12H, m), 2.32 (4H, bs), 2.57 (4H, m), 2.82(2H, t, J=6.5 Hz), 3.22 (4H, m), 3.43 (2H, t, J=6.5 Hz), 4.01 (1H, t,J=7.2 Hz), 4.78 (1H, m), 6.96 (1H, dd, J=2.5, 8.3 Hz), 7.05 (1H, d,J=8.3 Hz), 7.22 (10H, m), 7.64 (1H, d, J=2.5 Hz)

[0853] TSIMS(M/Z): 522(M+H)⁺

Example 1102-Allyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0854] In the same manner as in Example 51, the title compound (12 mg)was prepared from the compound (50 mg) obtained in Example 82 and allylbromide (21 mg).

[0855]¹H-NMR(CDCl₃) δ:2.30 (4H, bs), 2.57 (4H, m), 2.89 (2H, t, J=6.6Hz), 3.23 (4H, m), 3.49 (2H, t, J=6.6 Hz), 4.01 (1H, t, J=7.2 Hz), 4.20(2H, d, J=6.0 Hz), 5.23 (2H, m), 5.55 (1H, m), 6.99 (1H, dd, J=2.6, 8.5Hz), 7.06 (1h, d, J=8.5 Hz), 7.24 (10H, m), 7.65 (1H, d, J=2.6 Hz)

[0856] TSIMS(M/Z): 466(M+H)⁺

Example 1112-Cinnamyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0857] In the same manner as in Example 66, the title compound (27 mg)was prepared from the compound (50 mg) obtained in Example 82 andcinnamyl bromide (22 mg).

[0858]¹H-NMR(CDCl₃) δ:2.33 (4H, m), 2.90 (2H, t, J=6.6 Hz), 3.23 (4H,m), 3.54 (2H, t, J=6.6 Hz), 4.02 (2H, t, J=7.3 Hz), 4.36 (2H, d, J=6.4Hz), 6.25 (1H, dt, J=6.4, 15.0 Hz), 6.58 (1H, d, J=15.0 Hz), 7.00 (1H,dd, J=2.3, 8.2 Hz), 7.07 (1H, d, J=8.2 Hz), 7.27 (15H, m), 7.68 (1H, d,J=2,3 Hz)

[0859] TSIMS(M/Z): 542(M+H)⁺

Example 1127-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-phenyl-1-propyl)-3,4-dihydro-2H-isoquinolin-1-one

[0860] In the same manner as in Example 51, the title compound (11 mg)was prepared from the compound (30 mg) obtained in Example 82 and3-phenyl-propyl bromide (21 mg).

[0861]¹H-NMR(CDCl₃) δ:1.95 (2H, tt, J=6.6, 7.9 Hz), 2.30 (4H, m), 2.57(4H, t, J=4.8 Hz), 2.85 (2H, t, J=7.9 Hz), 2.88 (2H, t, J=6.6 Hz), 3.23(4H, t, J=4.8 Hz), 3.48 (2H, t, J=6.6 Hz), 3.61 (2H, t, J=6.6 Hz), 4.01(1H, t, J=7.1 Hz), 6.96 (1H, dd, J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz),7.17 (6H, m), 7.27 (10H, m), 7.64 (1H, d, J=7.5 Hz)

[0862] TSIMS(m/z): 544(M+H)⁺

Example 1137-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-phenetyl-3,4-dihydro-2H-isoquinolin-1-one

[0863] In the same manner as in Example 51, the title compound (76 mg)was prepared from the compound (30 mg) obtained in Example 82 and2-bromoethylbenzene (39 mg).

[0864]¹H-NMR(CDCl₃) δ:2.30 (4H, m), 2.57 (4H, t, J=4.8 Hz), 2.75 (2H, t,J=6.5 Hz), 2.88 (2H, t, J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.34 (2H, t,J=6.5 Hz), 3.48 (2H, t, J=6.6 Hz), 4.01 (1H, t, J=7.1 Hz), 6.96 (1H, dd,J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz), 7.17 (6H, m), 7.27 (10H, m),7.64 (1H, d, J=7.5 Hz)

[0865] FABMS(m/z): 530(M+H)⁺

Example 1142-(3,3-Diphenyl-1-propyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0866] In the same manner as in Example 51, the title compound (35 mg)was prepared from the compound (30 mg) obtained in Example 82 and3,3-diphenyl-1-propyl bromide (29 mg).

[0867]¹H-NMR(CDCl₃) δ:2.28-2.42 (6H, m), 2.57 (4H, t, J=4.8 Hz), 2.88(2H, t, J=7.8 Hz), 3.23 (4H, t, J=4.8 Hz), 3.42 (2H, t, J=6.4 Hz), 3.49(2H, t, J=7.8 Hz), 4.00 (2H, t, J=7.5 Hz), 6.95 (1H, dd, J=2.8, 8.3 Hz),7.00 (1H, d, J=8.3 Hz), 7.17 (5H, m), 7.27 (12H, m), 7.63 (1H, d, J=7.5Hz)

[0868] TSIMS(m/z): 620(M+H)⁺

Example 1157-(4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(2-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0869] In the same manner as in Example 66, the title compound (48 mg)was prepared from the compound (50 mg) obtained in Example 82 and2-methyl benzyl bromide (26 mg).

[0870]¹H-NMR(CDCl₃) δ:2.33 (3H, s), 2.35 (4H, m), 2.59 (4H, m), 2.83(2H, t, J=6.4 Hz), 3.27 (4H, m), 3.40 (2H, t, J=6.4 Hz), 3.42 (1H, t,J=7.1 Hz), 4.81 (2H, s), 7.00 (1H, dd, J=2.5, 8.5 Hz), 7.06 (1H, d,J=8.5 Hz), 7.24 (14H, m), 7.71 (1H, d, J=2.5 Hz)

[0871] TSIMS(M/Z): 530(M+H)⁺

Example 1167-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0872] In the same manner as in Example 66, the title compound (25 mg)was prepared from the compound (50 mg) obtained in Example 82 and3-methyl benzyl bromide (26 mg).

[0873]¹H-NMR(CDCl₃) δ:2.33 (7H, bs), 2.60 (4H, m), 2.84 (2H, t, J=6.7Hz), 3.26 (4H, m), 3.45 (2H, t, J=6.7 Hz), 4.02 (1H, t, J=7.3 Hz), 4.76(2H, s), 7.00 (1H, dd, J=2.8, 8.5 Hz), 7.05 (1H, d, J=8.5 Hz), 7.21(14H, m), 7.71 (1H, d, J=2.8 Hz)

[0874] TSIMS(M/Z): 530(M+H)⁺

Example 1177-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(4-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0875] In the same manner as in Example 66, the title compound (24 mg)was prepared from the compound (50 mg) obtained in Example 82 and4-methyl benzyl bromide (26 mg).

[0876]¹H-NMR(CDCl₃) δ:2.34 (7H, bs), 2.60 (4H, m), 2.83 (2H, t, J=6.5Hz), 3.25 (4H, m), 3.44 (2H, t, J=6.5 Hz), 4.02 (1H, t, J=7.0 Hz), 4.74(2H, s), 6.98 (1H, dd, J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz), 7.22(14H, m), 7.71 (1H, d, J=2.8 Hz)

[0877] TSIMS(M/Z): 530(M+H)⁺

Example 1182-(3,4-Dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0878] In the same manner as in Example 51, the title compound (30 mg)was prepared from the compound (50 mg) obtained in Example 82 and3,4-dimethylbenzyl chloride (20 mg).

[0879]¹H-NMR(CDCl₃) δ:2.24 (6H, s), 2.34 (4H, bs), 2.58 (4H, m), 2.83(2H, m), 3.25 (4H, m), 3.44 (2H, m), 4.01 (1H, m), 4.72 (2H, s), 7.17(15H, m), 7.71 (1H, d, J=2.5 Hz)

[0880] TSIMS(M/Z): 544(M+H)⁺

Example 1192-(2,5-Dimethylbenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0881] In the same manner as in Example 51, the title compound (28 mg)was prepared from the compound (52 mg) obtained in Example 82 and2,5-dimethylbenzyl chloride (28 mg).

[0882]¹H-NMR(CDCl₃) δ:2.28 (3H, s), 2.29 (3H, s), 2.30 (4H, m), 2.57(4H, t, J=4.8 Hz), 2.88 (2H, t, J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.48(2H, t, J=6.6 Hz), 4.01 (1H, t, J=7.1 Hz), 4.84 (2H, s), 6.96 (1H, dd,J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz), 7.17 (3H, m), 7.27 (11H, m)

[0883] TSIMS(m/z): 544(M+H)⁺

Example 1207-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(2,4,6-trimethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0884] In the same manner as in Example 51, the title compound (22 mg)was prepared from the compound (52 mg) obtained in Example 82 and2,4,6-trimethylbenzyl chloride (31 mg).

[0885]¹H-NMR(CDCl₃) δ:2.28 (3H, s), 2.29 (3H, s), 2.30 (7H, m), 2.57(4H, t, J=4.8 Hz), 2.88 (2H, t, J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.48(2H, t, J=6.6 Hz), 4.01 (1H, t, J=7.1 Hz), 4.85 (2H, s), 6.96 (1H, dd,J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz), 7.17 (3H, m), 7.27 (10H, m)

[0886] TSIMS(m/z): 558(M+H)⁺

Example 1217-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(1-phenylethyl)-3,4-dihydro-2H-isoquinolin-1-one

[0887] In the same manner as in Example 51, the title compound (29 mg)was prepared from the compound (50 mg) obtained in Example 82 and1-phenylethyl bromide (27 mg).

[0888]¹H-NMR(CDCl₃) δ:1.59 (3H, d, J=7.1 Hz), 2.34 (4H, bs), 2.59 (4H,m), 2.73 (2H, t, J=6.9 Hz), 3.08 (1H, m), 3.25 (4H, m), 3.35 (1H, m),4.02 (11H, t, J=7.0 Hz), 6.25 (1H, q, J=7.1 Hz), 6.98 (1H, dd, J=2.4,8.4 Hz), 7.03 (1H, d, J=8.4 Hz), 7.31 (15H, m), 7.72 (1H, d, J=2.4 Hz)

[0889] TSIMS(M/Z): 530(M+H)⁺

Example 1227-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0890] In the same manner as in Example 51, the title compound (44 mg)was prepared from the compound (50 mg) obtained in Example 82 and4-trifluoromethylbenzyl chloride (35 mg).

[0891]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.58 (4H, m), 2.88 (2H, t, J=6.6Hz), 3.25 (4H, m), 3.47 (2H, t, J=6.6 Hz), 4.02 (1H, t, J=7.2 Hz), 4.83(2H, s), 7.00 (1H, dd, J=2.5, 8.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.28(10H, m), 7.45 (2H, d, J=8.0 Hz), 7.59 (2H, d, J=8.0 Hz), 7.70 (1H, d,J=2.5 Hz)

[0892] TSIMS(M/Z): 584(M+H)⁺

Example 1237-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-trifluoromethylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0893] In the same manner as in Example 51, the title compound (41 mg)was prepared from the compound (50 mg) obtained in Example 82 and3-trifluoromethylbenzyl chloride (35 mg).

[0894]¹H-NMR(CDCl₃) δ:2.34 (4H, bs), 2.59 (4H, m), 2.88 (2H, t, J=6.6Hz), 3.26 (4H, m), 3.48 (2H, t, J=6.6 Hz), 4.04 (1H, t, J=7.2 Hz), 4.85(2H, s), 7.01 (1H, dd, J=2.5, 8.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.37(14H, m), 7.72 (1H, d, J=2.5 Hz)

[0895] TSIMS(M/Z): 584(M+H)⁺

Example 1247-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-fluorobenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0896] In the same manner as in Example 51, the title compound (11 mg)was prepared from the compound (50 mg) obtained in Example 82 and3-fluoro benzyl bromide (24 mg).

[0897]¹H-NMR(CDCl₃) δ:2.29-2.33 (4H, m), 2.58 (4H, t, J=5.0 Hz), 2.87(2H, t, J=6.6 Hz), 3.24 (4H, t, J=5.0 Hz), 3.46 (2H, t, J=6.6 Hz), 4.02(1H, t, J=7.4 Hz), 4.77 (2H, s), 6.94-7.11 (6H, m), 7.15-7.20 (2H, m),7.25-7.31 (8H, m), 7.69 (1H, d, J=2.5 Hz)

[0898] TSIMS(M/Z): 534(M+H)⁺

Example 1252-(3-Bromobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0899] In the same manner as in Example 51, the title compound (38 mg)was prepared from the compound (50 mg) obtained in Example 82 and3-bromo benzyl bromide (32 mg).

[0900]¹H-NMR(CDCl₃) δ:2.30-2.33 (4H, m), 2.57 (4H, t, J=4.6 Hz), 2.86(2H, t, J=6.7 Hz), 3.24 (4H, t, J=4.6 Hz), 3.46 (2H, t, J=6.7 Hz), 4.02(1H, t, J=7.5 Hz), 4.75 (2H, s), 6.99 (1H, dd, J=2.7, 8.4 Hz), 7.05 (1H,d, J=8.4 Hz), 7.16-7.21 (4H, m), 7.26-7.33 (8H, m), 7.40 (1H, d, J=7.8Hz), 7.47 (1H, s), 7.69 (1H, d, J=2.4 Hz)

[0901] TSIMS(M/Z): 596(M+H)⁺

Example 1262-(3,4-Dichlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0902] In the same manner as in Example 51, the title compound (44 mg)was prepared from the compound (50 mg) obtained in Example 82 and3,4-dichlorobenzyl chloride (26 mg).

[0903]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.57 (4H, m), 2.89 (2H, m), 3.25(4H, m), 3.44 (2H, m), 4.02 (1H, t, J=7.0 Hz), 4.73 (2H, s), 7.03 (1H,dd, J=2.5, 8.5 Hz), 7.07 (1H, d, J=8.5 Hz), 7.27 (13H, m), 7.69 (1H, d,J=2.5 Hz)

[0904] TSIMS(M/Z): 586(M+H)⁺

Example 1272-(2,4-Diochlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0905] In the same manner as in Example 51, the title compound (38 mg)was prepared from the compound (50 mg) obtained in Example 82 and2,4-dichlorobenzyl chloride (26 mg).

[0906]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.57 (4H, m), 2.91 (2H, m), 3.24(4H, m), 3.52 (2H, m), 4.02 (1H, t, J=6.9 Hz), 4.86 (2H, s), 7.05 (1H,dd, J=2.5, 8.5 Hz), 7.07 (1H, d, J=8.3 Hz), 7.24 (13H, m), 7.68 (1H, d,J=2.5 Hz)

[0907] TSIMS(M/Z): 586(M+H)⁺

Example 128 Methyl4-{7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-1-oxo-3,4-dihydro-2H-isoquinolin-2-ylmethyl}-benzoate

[0908] In the same manner as in Example 51, the title compound (80 mg)was prepared from the compound (100 mg) obtained in Example 82 andmethyl 4-(bromomethyl)benzoate (109 mg).

[0909]¹H-NMR(CDCl₃) δ:1.25 (3H, s), 2.30 (4H, m), 2.57 (4H, t, J=4.8Hz), 2.88 (2H, t, J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.48 (2H, t, J=6.6Hz), 4.01 (1H, t, J=7.1 Hz), 6.96 (1H, dd, J=2.8, 8.3 Hz), 7.04 (1H, d,J=8.3 Hz), 7.17 (3H, m), 7.27 (12H, m)

[0910] TSIMS(m/z): 574(M+H)⁺

Example 1297-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0911] In the same manner as in Example 51, the title compound (35 mg)was prepared from the compound (50 mg) obtained in Example 82 and3-methoxybenzyl chloride (28 mg).

[0912]¹H-NMR(CDCl₃) δ:2.34 (4H, bs), 2.59 (4H, m), 2.85 (2H, t, J=6.7Hz), 3.25 (4H, m), 3.46 (2H, t, J=6.7 Hz), 3.79 (3H, s), 4.02 (1H, t,J=6.9 Hz), 4.77 (2H, s), 6.87 (4H, m), 6.99 (1H, dd, J=2.5, 8.4 Hz),7.06 (1H, d, J=8.4 Hz), 7.27 (10H, m), 7.70 (1H, d, J=2.5 Hz)

[0913] TSIMS(M/Z): 546(M+H)⁺

Example 1302-(3,5-Dimethoxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0914] In the same manner as in Example 51, the title compound (40 mg)was prepared from the compound (50 mg) obtained in Example 82 and3,5-dimethoxybenzyl chloride (34 mg).

[0915]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.58 (4H, m), 2.85 (2H, t, J=6.4Hz), 3.25 (4H, m), 3.46 (2H, t, J=6.4 Hz), 3.77 (6H, s), 4.03 (1H, t,J=7.1 Hz), 4.72 (2H, s), 6.37 (1H, d, J=2.2 Hz), 6.48 (2H, d, J=2.2 Hz),6.99 (1H, dd, J=2.4, 8.5 Hz), 7.05 (1H, d, J=8.5 Hz), 7.27 (10H, m),7.70 (1H, d, J=2.4 Hz)

[0916] FABMS(M/Z): 576(M+H)⁺

Example 1317-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(3-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one

[0917] The compound (44 mg) obtained in Example 127 was dissolved indichloromethane (5 ml). The solution was cooled to 0° C. A 1.0 Mdichloromethane solution (0.24 ml) of boron tribromide was then added tothe solution. The mixture was stirred at room temperature for 2 hr. Asaturated aqueous sodium hydrogencarbonate solution was added to thereaction solution. The mixture was then extracted with dichloromethane.The organic layer was dried over anhydrous magnesium sulfate. Thesolvent was then removed by distillation. The residue was developed inpreparative TLC (chloroform:methanol=9:1) to give the title compound (24mg).

[0918]¹H-NMR(CDCl₃) δ:2.31 (4H, bs), 2.53 (4H, m), 2.67 (2H, t, J=6.6Hz), 3.15 (4H, m), 3.38 (2H, t, J=6.6 Hz), 4.00 (1H, t, J=7.1 Hz), 4.71(2H, s), 6.85 (4H, m), 7.22 (12H, m), 7.63 (1H, bs)

[0919] TSIMS(M/Z): 532(M+H)⁺

Example 1322-(3,5-Dihydroxybenzyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0920] In the same manner as in Example 131, the title compound (28 mg)was prepared from the compound (60 mg) obtained in Example 130 and a 1.0M aqueous dichloromethane solution (0.6 ml) of boron tribromide.

[0921]¹H-NMR(DMSO-d₆) δ:2.22 (4H, bs), 2.82 (2H, t, J=6.4 Hz), 3.11 (4H,bs), 3.39 (2H, t, J=6.4 Hz), 3.41 (1H, bs), 4.51 (2H, s), 6.07 (1H, s),6.14 (2H, s), 7.25 (13H, m)

[0922] TSIMS(M/Z): 548(M+H)⁺

Example 1332-(2-Hydroxy-2-phenylethyl)-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0923] In the same manner as in Example 51, the title compound (17 mg)was prepared from the compound (45 mg) obtained in Example 50 andstyrene oxide.

[0924]¹H-NMR(CDCl₃) δ:2.29-2.33 (4H, m), 2.57 (4H, br.t), 2.65-2.74 (2H,m), 3.23 (4H, br.t), 3.39-3.45 (1H, m), 3.39 (1H, dd, J=6.8, 14.1 Hz),3.96-4.03 (2H, m), 4.59 (1H, br.s), 5.11 (1H, dd, J=2.9, 7.1), 6.97-7.62(18H, m)

[0925] EIMS(M/Z): 545(M⁺)

Example 1342-(2-Biphenylmethyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one

[0926] In the same manner as in Example 51, the title compound (28 mg)was prepared from the compound (50 mg) obtained in Example 82 and2-(bromomethyl)biphenyl (32 mg).

[0927]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.58 (4H, m), 2.82 (4H, m), 3.24(4H, m), 4.02 (1H, t, J=7.0 Hz), 4.80 (2H, s), 6.98 (1H, dd, J=2.4, 8.0Hz), 7.31 (19H, m), 7.68 (1H, d, J=2.4 Hz)

[0928] TSIMS(M/Z): 592(M+H)⁺

Example 1357-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(tetrahydro-pyran-2-ylmethyl)-3,4-dihydro-2H-isoquinolin-1-one

[0929] In the same manner as in Example 51, the title compound (32 mg)was prepared from the compound (30 mg) obtained in Example 82 and2-(bromomethyl)tetrahydro-2H-pyran (19 mg).

[0930]¹H-NMR(CDCl₃) δ:1.31 (1H, m), 1.49 (2H, m), 1.67 (1H, d, J=12.7Hz), 1.84 (1H, m), 2.30 (4H, m), 2.57 (4H, t, J=4.8 Hz), 2.88 (2H, t,J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.37 (1H, m), 3.62 (3H, m), 3.85 (1H,dd, J=3.4, 13.7 Hz), 3.93 (1H, td, J=1.7, 11.2 Hz), 4.01 (1H, t, J=7.6Hz), 6.96 (1H, dd, J=2.8, 8.3 Hz), 7.04 (1H, d, J=8.3 Hz), 7.17 (3H, m),7.27 (4H, m), 7.64 (1H, d, J=7.5 Hz)

[0931] TSIMS(m/z): 524(M+H)⁺

Example 1367-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(thiazol-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one

[0932] In the same manner as in Example 51, the title compound (20 mg)was prepared from the compound (50 mg) obtained in Example 82 and4-chloromethylthiazole (19 mg).

[0933]¹H-NMR(CDCl₃) δ:2.32 (4H, bs), 2.56 (4H, m), 2.90 (2H, t, J=6.6Hz), 3.22 (4H, m), 3.68 (2H, t, J=6.6 Hz), 4.02 (1H, t, J=7.1 Hz), 4.94(2H, s), 6.99 (1H, dd, J=2.6, 8.3 Hz), 7.06 (1H, d, J=8.3 Hz), 7.27(11H, m), 7.66 (1H, d, J=2.6 Hz), 8.76 (1H, d, J=2.0 Hz)

[0934] TSIMS(M/Z): 523(M+H)⁺

Example 1377-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-[(4-methylthiazol)-5-yl]methyl-3,4-dihydro-2H-isoquinolin-1-one

[0935] In the same manner as in Example 51, the title compound (33 mg)was prepared from the compound (50 mg) obtained in Example 82 step and5-chloromethyl-4-methylthiazole (20 mg).

[0936]¹H-NMR(CDCl₃) δ:2.33 (4H, bs), 2.52 (3H, s), 2.58 (4H, m), 2.88(2H, t, J=6.5 Hz), 3.24 (4H, m), 3.51 (2H, t, J=6.5 Hz), 4.01 (1H, t,J=7.1 Hz), 4.90 (2H, s), 6.99 (1H, dd, J=2.5, 8.3 Hz), 7.27 (10H, m),7.67 (1H, d, J=2.5 Hz), 8.64 (1H, s)

[0937] TSIMS(M/Z): 537(M+H)⁺

Example 1387-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-4-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one

[0938] In the same manner as in Example 51, the title compound (8 mg)was prepared from the compound (30 mg) obtained in Example 82 and4-picolyl chloride hydrochloride (14 mg).

[0939]¹H-NMR(CDCl₃) δ:2.30 (4H, m), 2.57 (4H, t, J=4.8 Hz), 2.88 (2H,bt, J=6.2 Hz), 3.23 (4H, t, J=4.8 Hz), 3.61 (2H, bt, J=6.2 Hz), 4.01(1H, t, J=7.1 Hz), 4.93 (2H, s), 6.98 (1H, dd, J=2.4, 8.3 Hz), 7.05 (1H,d, J=8.3 Hz), 7.17 (3H, m), 7.26 (8H, m), 7.38 (1H, d, J=7.8 Hz), 7.61(2H, m), 8.53 (1H, m)

[0940] TSIMS(m/z): 517(M+H)⁺

Example 1397-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-(pyridine-2-yl)methyl-3,4-dihydro-2H-isoquinolin-1-one

[0941] In the same manner as in Example 51, the title compound (33 mg)was prepared from the compound (30 mg) obtained in Example 82 and2-(chloromethyl)-pyridine hydrochloride (17 mg).

[0942]¹H-NMR(CDCl₃) δ:2.30 (4H, m), 2.57 (4H, t, J=4.8 Hz), 2.88 (2H, t,J=6.6 Hz), 3.23 (4H, t, J=4.8 Hz), 3.61 (2H, t, J=6.6 Hz), 4.01 (1H, t,J=7.1 Hz), 4.90 (2H, s), 6.98 (1H, dd, J=2.4, 8.3 Hz), 7.05 (1H, d,J=8.3 Hz), 7.17 (3H, m), 7.26 (8H, m), 7.38 (1H, d, J=7.8 Hz), 7.63 (1H,dt, J=1.7, 7.8 Hz), 7.68 (1H, d, J=2.5 Hz), 8.53 (1H, d, J=4.4 Hz)

[0943] TSIMS(m/z): 517(M+H)⁺

Example 140 6-[4-(3,3-Diphenyl-1-propyl)piperazin-1-yl]-2-phenyl-2,3-dihydro-1H-isoindol-1-one

[0944] (a) Concentrated sulfuric acid (12 ml) was added to a solution of2-methyl-5-nitrobenzoic acid (10.87 g) in ethanol (60 ml). The mixturewas heated under reflux overnight. The reaction solution wasconcentrated under the reduced pressure. Water was then added to theresidue. The mixture was extracted with diethyl ether. The extract waswashed with water and saturated saline, and then dried over anhydrousmagnesium sulfate. The solvent was then removed by distillation underthe reduced pressure. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate=4:1) to give ethyl2-methyl-5-nitrobenzoate (11.86 g).

[0945]¹H-NMR(CDCl₃) δ:1.44 (3H, t, J=7.1 Hz), 2.72 (3H, s), 4.42 (2H, q,J=7.1 Hz), 7.43 (1H, d, J=8.4 Hz), 8.24 (1H, dd, J=2.5, 8.4 Hz), 8.76(1H, d, J=2.5 Hz)

[0946] EIMS(M/Z): 209(M⁺)

[0947] (b) N-bromosuccinimide (4.63 g) and azobisisobutyronitrile (0.49g) were added to a solution of the compound (4.18 g), obtained in step(a) just above, in a carbon tetrachloride (200 ml). The mixture washeated under reflux overnight at 90° C. The temperature of the reactionsolution was returned to room temperature. Chloroform was added thereto.The mixture was washed with water, and then dried over anhydrousmagnesium sulfate. The solvent was removed by distillation under thereduced pressure. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=10:1) to give ethyl2-bromomethyl-5-nitrobenzoate (3.34 g).

[0948]¹H-NMR(CDCl₃) δ:1.47 (3H, t, J=7.1 Hz), 4.47 (2H, q, J=7.1 Hz),5.00 (2H, s), 7.68 (1H, d, J=8.5 Hz), 8.33 (1H, dd, J=2.5, 8.5 Hz), 8.81(1H, d, J=2.5 Hz)

[0949] FABMS(M/Z): 288(M+H)⁺

[0950] (c) Aniline (1.00 g) and diisopropylethylamine (1.52 g) wereadded to a solution of the compound (2.82 g), obtained in step (b) justabove, in ethanol (45 ml). The mixture was stirred at room temperaturefor 4 hr. The reaction solution was concentrated under the reducedpressure. A 0.1 N aqueous citric acid solution was then added to theresidue. The mixture was extracted with chloroform. The extract waswashed with saturated saline, and then dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=10:1) to give ethyl5-nitro-2-phenylaminomethylbenzoate (2.52 g).

[0951]¹H-NMR(CDCl₃) δ:1.45 (3H, t, J=7.1 Hz), 4.41-4.48 (3H, m),4.81-4.82 (2H, m), 6.55 (2H, d, J=8.2 Hz), 6.73 (1H, t, J=7.3 Hz), 7.16(2H, t, J=8.0 Hz), 7.78 (1H, d, J=8.6 Hz), 8.28 (1H, dd, J=2.5, 8.6 Hz),8.82 (1H, d, J=2.5 Hz)

[0952] TSIMS(M/Z): 300(M−H)⁺

[0953] (d) 5% palladium-carbon (50 mg) was added to a suspension of thecompound (1.5 g), obtained in step (c) just above, in ethanol (12.5 ml),followed by catalytic reduction. The mixture was stirred at roomtemperature overnight. The reaction solution was filtered throughCelite. The solvent was then removed from the filtrate by distillationunder the reduced pressure. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=4:1) to give ethyl5-amino-2-phenylaminomethylbenzoate (1.22 g).

[0954]¹H-NMR(CDCl₃) δ:1.35 (3H, t, J=7.1 Hz), 3.72 (2H, brs), 4.29-4.40(3H, m), 4.49 (2H, s), 6.61-6.69 (3H, m), 6.76 (1H, dd, J=2.6, 8.2 Hz),7.14 (2H, t, J=7.9 Hz), 7.26-7.28 (2H, m)

[0955] TSIMS(M/Z): 271(M+H)⁺

[0956] (e) Sodium ethoxide (0.32 g) was added to a solution of thecompound (1.14 g), obtained in step (d) just above, in ethanol (210 ml).The mixture was stirred at 60° C. for 1.5 hr. The reaction solution wasconcentrated under the reduced pressure. A saturated aqueous sodiumhydrogencarbonate solution was then added to the residue. The mixturewas extracted with chloroform. The organic layer was then washed withsaturated saline, and then was dried over anhydrous magnesium sulfate.The solvent was then removed by distillation under the reduced pressure.The precipitated crystals were collected by suction filtration, washedwith hexane, and then dried to give6-amino-2-phenyl-2,3-dihydro-1H-isoindol-1-one (0.88 g).

[0957]¹H-NMR(CDCl₃) δ:3.87 (2H, brs), 4.77 (2H, s), 6.91 (1H, dd, J=2.3,8.3 Hz), 7.14-7.22 (2H, m), 7.28 (1H, d, J=8.0 Hz), 7.42 (2H, t, J=8.0Hz), 7.86 (2H, d, J=8.0 Hz)

[0958] EIMS(M/Z): 224(M⁺)

[0959] (f) Bis(2-chloroethyl)amine hydrochloride (57 mg) was added to asolution of the compound (45 mg), obtained in step (e) just above, inn-butanol (2 ml). The mixture was stirred at 110° C. for 139 hr. Thereaction solution was concentrated under the reduced pressure. Theresidue was then purified by column chromatography on silica gel(chloroform:methanol=5:1) to give2-phenyl-6-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-1-one hydrochloride(26 mg).

[0960]¹H-NMR(CD₃OD) δ:3.36-3.38 (4H, m), 3.45-3.48 (4H, m), 4.92 (2H,s), 7.22 (1H, t, J=7.4 Hz), 7.37-7.46 (4H, m), 7.56 (1H, d, J=8.3 Hz),7.84 (2H, dd, J=1.1, 8.9 Hz)

[0961] TSIMS(M/Z): 294(M+H)⁺

[0962] (g) Potassium carbonate (42 mg) and 3,3-diphenyl-1-propyl bromide(29 mg) were added to a solution of the compound (18 mg), obtainedinstep (f) just above, in N,N-dimethylformamide (1 ml). The mixture wasstirred at 50° C. for 6 hr. The temperature of the system was returnedto room temperature. A 0.1 N aqueous citric acid solution was then addedthereto. The mixture was extracted with chloroform. The organic layerwas washed with saturated saline, and then dried over anhydrousmagnesium sulfate. The solvent was then removed by distillation underthe reduced pressure. The residue was purified by column chromatographyon silica gel (hexane ethyl acetate=1:1) to give the title compound (11mg).

[0963]¹H-NMR(CDCl₃) δ:2.27-2.39 (4H, m), 2.60 (4H, t, J=4.9 Hz), 3.28(4H, t, J=4.9 Hz), 4.03 (1H, t, J=7.3 Hz), 4.78 (2H, s), 7.15-7.20 (4H,m), 7.21-7.32 (8H, m), 7.35-7.46 (4H, m), 7.86 (2H, dd, J=1.1, 8.8 Hz)

[0964] TSIMS(M/Z): 488(M+H)⁺

Example 141 2-Benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one

[0965] (a) 4-Methoxybenzylamine (8.3 g) was added to homophthalicanhydride (8.1 g). The mixture was stirred at 180° C. overnight. Waterwas added to the reaction solution. The mixture was then extracted withethyl acetate. The organic layer was then dried over anhydrous magnesiumsulfate. The solvent was removed by distillation under the reducedpressure. The residue was purified by column chromatography on silicagel (hexane:ethyl acetate=8:2) to give2-(4-methoxybenzyl)-4H-isoquinoline-1,3-dione (11.8 g).

[0966]¹H-NMR(CDCl₃) δ:3.78 (3H, s), 4.05 (2H, s), 5.13 (2H, s), 6.83(2H, s), 7.41 (5H, m), 8.22 (1H, m)

[0967] EIMS(M/Z): 281(M⁺)

[0968] (b) The compound (10.0 g) obtained in step (a) just above wasdissolved in N,N-dimethylformamide (40 ml). Sodium hydride (4.2 g) wasadded under cooling at 0° C. to the solution. The mixture was stirredfor 20 min. Thereafter, methyl iodide (14.9 g) was added, and themixture was stirred at room temperature for 4 hr. Ethyl acetate andwater were added to the reaction solution, followed by stirring for 5min. The mixture was extracted with ethyl acetate. The organic layer wasthen dried over anhydrous magnesium sulfate. The solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography on silica gel (hexane:ethylacetate=1:1) to give2-(4-methoxybenzyl)-4,4-dimethyl-4H-isoquinoline-1,3- dione (10.9 g).

[0969]¹H-NMR(CDCl₃) δ:1.61 (6H, s), 3.77 (3H, s), 5.13 (2H, s), 6.83(2H, m), 7.43 (4H, m), 7.62 (1H, m), 8.23 (1H, m)

[0970] EIMS(M/Z): 309(M⁺)

[0971] (c) The compound (6.0 g) obtained in step (b) just above wasdissolved in a mixed solvent (acetonitrile:water 4:1) (40 ml).Diammonium cerium nitrate (26.6g) was added to the solution. The mixturewas stirred at room temperature for 3 hr. The reaction solution wasextracted with ethyl acetate. The organic layer was then dried overanhydrous magnesium sulfate. The solvent was then removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=8:2) to give4,4-dimethyl-4H-isoquinoline-1,3-dione (10.9 g).

[0972]¹H-NMR(CDCl₃) δ:1.67 (6H, s), 7.47 (2H, m), 7.68 (1H, m), 8.23(1H, m), 8.43 (1H, bs)

[0973] FABMS(M/Z): 190(M+H)⁺

[0974] (d) The compound (2.0 g) obtained in step (c) just above wasdissolved in methanol (100 ml). Sodium boron hydride (1.7 g) was addedto the solution. The mixture was stirred at room temperature for 3 hr.Hydrochloric acid-methanol (50 ml) was added to the reaction solution,and the mixture was stirred at room temperature for one hr. The reactionsolution was then extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was then removed bydistillation under the reduced pressure. The residue was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=1:1) to give3-methoxy-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.8 g).

[0975]¹H-NMR(CDCl₃) δ:1.32 (3H, s), 1.50 (3H, s), 3.36 (3H, s), 4.27(1H, d, J=4.6 Hz), 7.34 (2H, m), 7.53 (1H, m), 7.73 (1H, bs), 8.09 (1H,m)

[0976] EIMS(M/Z): 205(M⁺)

[0977] (e) The compound (1.3 g) obtained in step (d) just above wasdissolved in diethyl ether(15 ml). Phosphorus pentachloride (1.1 g) wasadded to the solution. The mixture was stirred at room temperature for30 min. The solvent was then removed by distillation under the reducedpressure. Glyme (20 ml) and sodium boron hydride (1.1 g) were added tothe residue. The mixture was stirred at room temperature for one hr.Water was added to the reaction solution, followed by stirring. Themixture was then extracted with ethyl acetate. The organic layer wasthen dried over anhydrous magnesium sulfate. The solvent was thenremoved by distillation under the reduced pressure. The residue waspurified by column chromatography on silica gel(chloroform:methanol=30:1) to give4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.8 g).

[0978]¹H-NMR(CDCl₃) δ: 1.36 (6H, s), 3.33 (2H, d, J=3.0 Hz), 6.51 (1H,bs), 7.35 (2H, m), 7.50 (1H, m), 8.09 (1H, m)

[0979] TSIMS(M/Z): 176(M+H)⁺

[0980] (f) In the same manner as in step (c) of Example 1,4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (450 mg) wasprepared from the compound (600 mg) obtained in step (e) just above.

[0981]¹H-NMR(CDCl₃) δ:1.43 (6H, s), 3.40 (2H, d, J=3.1 Hz), 7.54 (1H, d,J=8.6 Hz), 8.35 (1H, dd, J=2.5, 8.6 Hz), 8.93 (1H, d, J=2.5 Hz)

[0982] EIMS(M/Z): 220(M⁺)

[0983] (g) In the same manner as in step (d) of Example 1,7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (340 mg) wasprepared from the compound (450 mg) obtained in step (f) just above.

[0984]¹H-NMR(CDCl₃) δ:1.31 (6H, s), 3.27 (2H, d, J=2.9 Hz), 6.26 (1H,bs), 6.83 (1H, dd, J=2.2, 8.0 Hz), 7.12 (1H, d, J=8.0 Hz), 7.39 (1H, d,J=2.2 Hz)

[0985] FABMS(M/Z): 191(M+H)⁺

[0986] (h) In the same manner as in step (e) of Example 1,4,4-dimethyl-7-piperazin-1-yl-3,4-dihydro-2H-isoquinolin-1-one (340 mg)was prepared from the compound (480 mg) obtained in step (g) just above.

[0987]¹H-NMR(CDCl₃) δ:1.32 (6H, s), 3.03 (4H, m), 3.19 (4H, m), 3.28(2H, d, J=3.0 Hz), 6.36 (1H, dd, J=2.9, 8.6 Hz), 7.22 (1H, d, J=8.6 Hz),7.62 (1H, d, J=2.9 Hz)

[0988] EIMS(M/Z): 259(M⁺)

[0989] (i) In the same manner as in step (f) of Example 1,7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one(250 mg) was prepared from the compound (400 mg) obtained in step (h)just above and 3,3-diphenyl-1-propyl bromide (500 mg).

[0990]¹H-NMR(CDCl₃) δ:1.32 (6H, s), 2.20 (4H, bs), 2.57 (4H, m), 3.25(4H, m), 3.28 (2H, d, J=3.1 Hz), 4.02 (1H, t, J=7.1 Hz), 6.20 (1H, bs),7.05 (1H, dd, J=2.8, 8.5 Hz), 7.24 (11H, nm), 7.62 (1H, d, J=2.8 Hz)

[0991] EIMS(M/Z): 453(M⁺)

[0992] (j) In the same manner as in Example 51, the title compound (20mg) was prepared from the compound (50 mg) obtained in step (i) andbenzyl bromide (20 mg).

[0993]¹H-NMR(CDCl₃) δ:1.18 (6H, s), 2.34 (4H, bs), 2.58 (4H, m), 3.19(2H, s), 3.26 (4H, m), 4.02 (1H, t, J=7.4 Hz), 4.79 (2H, s), 7.00 (1H,dd, J=2.8, 8.7 Hz), 7.16 (1H, d, J=8.7 Hz), 7.27 (14H, m), 7.73 (1H, d,J=2.8 Hz)

[0994] FABMS(M/Z): 544(M+H)⁺

[0995] The compounds prepared in the above examples had the followingrespective structures.

Tablet Compound of Example 8 2.5 g Lactose  12 g 6% HPC lactose   8 gPotato starch   2 g Magnesium stearate 0.5 g Total  25 g

[0996] All the above ingredients were intimately mixed together, and themixture was compressed into 1000 tablets.

Preparation Example 2

[0997] Capsule Compound of Example 127 2.5 g Lactose  18 g Potato starch  4 g Magnesium stearate 0.5 g Total  25 g

[0998] All the above ingredients were intimately mixed together, and themixture was filled into 1000 hard capsules.

Test Example 1

[0999] Inhibitory activity against biosynthesis of triglycerides Theinhibitory activity of the compounds according to the present inventionagainst the biosynthesis of triglycerides were studied using cell strainHepG2 derived from human hepatoma.

[1000] The test was carried out by the method of Nagata et al. (Biochem.Pharmacol., 40, 843 (1990)) and the method of Furukawa et al. (J. Biol.Chem., 267, 22630 (1992)) which had been partly modified. Specifically,HepG2 cells were cultivated in a Dulbecco's modified Eagle's medium(DMEM), containing 10% fetal calf serum (FCS), 100 units/ml penicillin,and 100 μg/ml streptomycin, placed in 96-well plates. Thereafter, themedium was replaced with DMEM containing 1% bovine serum albumin, andthe test compound was simultaneously added to a final concentration of 3μM or was not added, followed by cultivation. Three hr after thereplacement of the medium, ¹⁴C-acetic acid was added to a finalconcentration of 1 mM, followed by cultivation for additional 4 hr. Thecells were washed with a phosphate buffer (pH 7.5) containing 150 mMsodium chloride. Thereafter, lipid within the cells was extracted withn-butanol. After the extraction, the extract was evaporated to drynessunder a nitrogen gas stream. The residue was dissolved in a small amountof chloroform. The solution was developed in thin-layer chromatography(developing solvent petroleum ether:diethyl ether:acetic acid=90:15:3),and a ¹⁴C-triglyceride fraction was isolated. The amount of¹⁴C-triglycerides produced was then quantitatively determined with aliquid scintillation counter (Beckman, LS-6500).

[1001] The inhibition (%) of the biosynthesis of triglycerides wascalculated by the following equation:

[1002] Inhibition (%) of biosynthesis of triglycerides={1−(amount of¹⁴C-triglycerides produced in the presence of drug)/(amount of¹⁴C-triglycerides produced in the absence of drug)}×100

Test Example 2 Inhibitory Activity Against Secretion of Apolipoprotein B

[1003] The inhibitory activity of the compounds according to the presentinvention against the secretion of apolipoprotein B was studied usingcell strain HepG2 derived from human hepatoma.

[1004] The test was carried out by the method of Nagata et al. (Biochem.Pharmacol., 40, 843 (1990)) and the method of Furukawa et al. (J. Biol.Chem., 267, 22630 (1992)) which had been partly modified. Specifically,HepG2 cells were cultivated in a Dulbecco's modified Eagle's medium(DMEM), containing 10% fetal calf serum (FCS), 100 units/ml penicillin,and 100 μg/ml streptomycin, placed in 96-well plates. Thereafter, themedium was replaced with DMEM containing 1% bovine serum albumin, andthe test compound was simultaneously added to a final concentration of 3μM or not added, followed by cultivation. Three hr after the replacementof the medium, acetic acid was added to a final concentration of 1 mM,followed by cultivation for additional 4 hr. The amount ofapolipoprotein B secreted in the supernatant of the culture thusobtained was quantitatively determined by the sandwich ELISA method. Inthis case, goat anti-human apolipoprotein B polyclonal antibody(CHEMICON) was used as a primary antibody, and mouse anti-humanapolipoprotein B monoclonal antibody peroxidase conjugate (BIOSYS) wasused as a secondary antibody.

[1005] The inhibition (%) against the secretion of apolipoprotein B wascalculated by the following equation:

[1006] Inhibition (%) of secretion of apolipoprotein B={1−(amount ofapolipoprotein B secreted in the presence of drug)/(amount ofapolipoprotein B secreted in the absence of drug)}×100

[1007] For the compounds obtained in Examples 5, 8, 30, and 68, theinhibition against the secretion of apolipoprotein B and the inhibitionagainst the biosynthesis of triglycerides were determined by TestExamples 1 and 2. The results are shown in Table 1. Inhibition (%)Compounds of examples Apolipoprotein B Triglycerides  5 56 90  8 70 7930 68 89 68 61 64

[1008] It was demonstrated that the novel nitrogen-containingheterocyclic ring compounds according to the present invention had theinhibitory activity against the biosynthesis of triglycerides and theinhibitory activity against the secretion of apolipoprotein B in theliver.

Test Example 3 Acute Toxicity Test

[1009] An acute toxicity test was carried out using mice and rats by aconventional method. Specifically, the compound of Example 8 was orallyadministered at a dose of 200 mg/kg to ddY mice (male) or wistar rats(male), and the mice and the rats were observed for 8 days. As a result,in all the cases, the mice and the rats survived, and any change ingeneral states, such as a reduction in body weight, did not occur.

What is claimed is:
 1. A compound represented by formula (I) andpharmaceutically acceptable salt and solvate thereof:

wherein A represents group —CR¹R²—(CH₂)₁— wherein R¹ and R², which maybe the same or different, represent a hydrogen atom or alkyl having 1 to6 carbon atoms and i is an integer of 0 or 1, —CH═CH—, —O—CH₂—, or—S(O)_(j)—CH₂— wherein j is an integer of 0 to 2; B represents ahydrogen or halogen atom; X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵,which may be the same or different, each represent a hydrogen atom orphenyl, provided that any one of R³, R⁴, and R⁵ represents phenyl andone or more hydrogen atoms on phenyl may be substituted by a halogenatom, hydroxyl, nitro, phenyl, or alkoxy having 1 to 6 carbon atoms,—NR⁶R⁷ wherein R⁶and R⁷, which may be the same or different, eachrepresent a hydrogen atom, phenyl, or benzyl,—(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is an integer of 0 to2, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8 carbonatoms, optionally substituted phenyl, optionally substituted cinnamyl,or a five- or six-membered heteroaromatic ring containing up to twohetero atoms; Y represents —(CH₂)_(q)— wherein q is an integer of 1 to6, —CH═CH—, NR⁸— wherein R⁸ represents a hydrogen atom or alkyl having 1to 6 carbon atoms, an oxygen atom, or a bond; Z represents carbonyl or abond; K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond; L represents —CH═CH— or a bond; and M represents ahydrogen atom, optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl, an optionally substituted five- or six-membered,saturated or unsaturated heterocyclic ring containing up to two heteroatoms, optionally substituted biphenyl, or optionally substituteddiphenylmethyl.
 2. The compound according to claim 1, wherein Arepresents group —CR¹R²—(CH₂)₁— wherein R¹ and R² each represent ahydrogen atom and i is an integer of 0 or 1; B represents a hydrogen orhalogen atom; X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are asdefined in claim 1, —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined inclaim 1, —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as definedin claim 1, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8carbon atoms, optionally substituted phenyl, optionally substitutedcinnamyl, or a five- or six-membered heteroaromatic ring containing upto two hetero atoms; Y represents —(CH₂)_(q), wherein q is an integer of1 to 6, —NH—, an oxygen atom, or a bond; Z represents carbonyl or abond; K represents optionally substituted alkylene having 1 to 6 carbonatoms or a bond; L represents —CH═CH— or a bond; and M represents ahydrogen atom, optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl, an optionally substituted, five- or six-membered,saturated or unsaturated heterocyclic ring containing up to two heteroatoms, optionally substituted biphenyl, or optionally substituteddiphenylmethyl.
 3. The compound according to claim 1, which isrepresented by formula (II):

wherein A represents group —CR¹R²—(CH₂)_(i)— wherein R¹, R², and i eachare as defined in claim 1, —CH═CH—, —O—CH₂—, or —S(O)₃—CH₂— wherein j isas defined in claim 1; B represents a hydrogen or halogen atom; Xrepresents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as defined in claim1, —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined in claim 1,—(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as defined in claim1, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8 carbonatoms, optionally substituted phenyl, optionally substituted cinnamyl,or a five- or six-membered heteroaromatic ring containing up to twohetero atoms; Y represents —(CH₂)_(q), wherein q is as defined in claim1, —NH—, an oxygen atom, or a bond; Z represents carbonyl or a bond; Krepresents optionally substituted alkylene having 1 to 6 carbon atoms ora bond; L represents —CH═CH— or a bond; and M represents a hydrogenatom, optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl, an optionally substituted five- or six-membered,saturated or unsaturated heterocyclic ring containing up to two heteroatoms, optionally substituted biphenyl, or optionally substituteddiphenylmethyl, provided that compounds, wherein —K—L—M represents —H,are excluded.
 4. The compound according to claim 3, wherein A representsgroup —CR¹R²—(CH₂)_(i)— wherein R¹ and R² each represent a hydrogen atomand i is an integer of 0 or 1; B represents a hydrogen or halogen atom;X represents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as defined inclaim 1, —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined in claim 1,—(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as defined in claim1, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8 carbonatoms, optionally substituted phenyl, optionally substituted cinnamyl,or a five- or six-membered heteroaromatic ring containing up to twohetero atoms; Y represents —(CH₂)_(q), wherein q is as defined in claim1, —NH—, an oxygen atom, or a bond; Z represents carbonyl or a bond; Krepresents optionally substituted alkylene having 1 to 6 carbon atoms ora bond; L represents —CH═CH— or a bond; and M represents a hydrogenatom, optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl, an optionally substituted, five- or six-membered,saturated or unsaturated heterocyclic ring containing up to two heteroatoms, optionally substituted biphenyl, or optionally substituteddiphenylmethyl.
 5. The compound according to claim 3, wherein Arepresents group —CR¹R²—(CH₂)_(i)— wherein R¹, R², and i each are asdefined in claim 1, —CH═CH—, —O—CH₂—, or —S(O)_(j)—CH₂— wherein j is asdefined in claim 1; B represents a hydrogen or halogen atom; Xrepresents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as defined in claim1 or —(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as defined inclaim 1; Y represents —(CH₂)_(q), wherein q is as defined in claim 1,—NH—, an oxygen atom, or a bond; Z represents carbonyl or a bond; Krepresents optionally substituted alkylene having 1 to 6 carbon atoms ora bond; L represents —CH═CH— or a bond; and M represents a hydrogenatom, optionally substituted alkyl having 1 to 6 carbon atoms,optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionallysubstituted phenyl, an optionally substituted five- or six-membered,saturated or unsaturated heterocyclic ring containing up to two heteroatoms, optionally substituted biphenyl, or optionally substituteddiphenylmethyl.
 6. The compound according to claim 3, wherein Arepresents group —CR¹R²—(CH₂)_(i)— wherein R¹, R², and i each are asdefined in claim 1, —CH═CH—, —O—CH₂—, or —S(O)_(j)—CH₂— wherein j is asdefined in claim 1; B represents a hydrogen or halogen atom; Xrepresents —CR³R⁴R⁵ wherein R³, R⁴, and R⁵ each are as defined in claim1, —NR⁶R⁷ wherein R⁶ and R⁷ each are as defined in claim 1,—(CH₂—CH═C(CH₃)—CH₂)_(p)—CH₂CH═C(CH₃)₂ wherein p is as defined in claim1, alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8 carbonatoms, optionally substituted phenyl, optionally substituted cinnamyl,or a five- or six-membered heteroaromatic ring containing up to twohetero atoms; Y represents —(CH₂)_(q), wherein q is as defined in claim1, —NH—, an oxygen atom, or a bond; Z represents carbonyl or a bond; Krepresents optionally substituted alkylene having 1 to 3 carbon atoms ora bond; L represents —CH═CH— or a bond; and M represents a hydrogenatom, optionally substituted cycloalkyl having 3 to 8 carbon atoms,optionally substituted phenyl, or an optionally substituted five- orsix-membered, saturated or unsaturated heterocyclic ring containing upto two hetero atoms.
 7. The compound or salt thereof according to claim3, which is 2-cyclohexyl-6-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-2,3-dihydro-1H-isoindol-1-one,2-benzyl-7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,2-(4-chlorobenzyl)-7-[4-(3,3-diphenyl-1-propyl)-piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one,7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methylbenzyl)-3,4-dihydro-2H-isoquinolin-1-one,7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(3-hydroxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one,or7-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-2-(4-thiazolylmethyl)-3,4-dihydro-2H-isoquinolin-1-one.8. A pharmaceutical composition comprising an effective amount of thecompound or a pharmacologically acceptable salt or solvate thereofaccording to any one of claims 1 to 7 and a pharmacologically acceptablecarrier.
 9. The pharmaceutical composition according to claim 8, whichis an inhibitor against the secretion of a lipoprotein containingapolipoprotein B.
 10. The pharmaceutical composition according to claim8, which is an inhibitor against the biosynthesis of triglycerides. 11.The pharmaceutical composition according to claim 8, which is aprophylactic or therapeutic agent for hyperlipidemia.
 12. Thepharmaceutical composition according to claim 8, which is a prophylacticor therapeutic agent for arteriosclerotic diseases.
 13. Thepharmaceutical composition according to claim 8, which is a prophylacticor therapeutic agent for pancreatitis.
 14. A method for preventing ortreating hyperlipidemia, comprising administering an effective amount ofthe compound and pharmacologically acceptable salt and solvate thereofaccording to any one of claims 1 to 7 to animals including human beings.15. A method for preventing or treating arteriosclerotic diseases,comprising administering an effective amount of the compound andpharmacologically acceptable salt and solvate thereof according to anyone of claims 1 to 7 to animals including human beings.
 16. A method forpreventing or treating pancreatitis, comprising administering aneffective amount of the compound and pharmacologically acceptable saltand solvate thereof according to any one of claims 1 to 7 to animalsincluding human beings.
 17. Use of the compound and pharmacologicallyacceptable salt and solvate thereof according to any one of claims 1 to7 for the production of inhibitors against the secretion of lipoproteincontaining apolipoprotein B.
 18. Use of the compound andpharmacologically acceptable salt and solvate thereof according to anyone of claims 1 to 7 for the production of inhibitors against thebiosynthesis of triglycerides.
 19. Use of the compound andpharmacologically acceptable salt and solvate thereof according to anyone of claims 1 to 7 for the production of prophylactic or therapeuticagents for hyperlipidemia.
 20. Use of the compound and pharmacologicallyacceptable salt and solvate thereof according to any one of claims 1 to7 for the production of prophylactic or therapeutic agents forarteriosclerotic diseases.
 21. Use of the compound and pharmacologicallyacceptable salt and solvate thereof according to any one of claims 1 to7 for the production of prophylactic or therapeutic agents forpancreatitis.